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Hybrid lipid bioelectronic membranes

Posted in Bioengineering & reverse engineering design, BioTechnology - Venture Creation, Cell Biology, Signaling & Cell Circuits, Curation, Electrophysiology, Innovations, Innovations in Neurophysiology & Neuropsychology, Ionic Transporters Na+, Lipid metabolism, Lipidomics, Lipids, Liposome, Metabolism, Microvesicle, Na-K transport, Nephrology, Neurohumoral Transmission, Physics, Proteins, Proteomics, Signaling, Signaling & Cell Circuits, Synaptic vesicle, tagged bioengineering, Biological sciences, Biophysics, Biotechnology, ion transport, lipid bilayers on December 14, 2015| Leave a Comment »

Hybrid lipid bioelectronic membranes

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Hybrid solid-state chips and biological cells integrated at molecular level

Biological ion channels combine with solid-state transistors to create a new kind of hybrid bioelectronics. Imagine chips with dog-like capability to taste and smell, or even recognize specific molecules.
http://www.kurzweilai.net/hybrid-solid-state-chips-and-biological-cells-integrated-at-molecular-level

http://www.kurzweilai.net/images/biocell-CMOS-.jpg

Illustration depicting a biocell attached to a CMOS integrated circuit with a membrane containing sodium-potassium pumps in pores. Energy is stored chemically in ATP molecules. When the energy is released as charged ions (which are then converted to electrons to power the chip at the bottom of the experimental device), the ATP is converted to ADP + inorganic phosphate. (credit: Trevor Finney and Jared Roseman/Columbia Engineering)

Columbia Engineering researchers have combined biological and solid-state components for the first time, opening the door to creating entirely new artificial biosystems.

In this experiment, they used a biological cell to power a conventional solid-state complementary metal-oxide-semiconductor (CMOS) integrated circuit. An artificial lipid bilayer membrane containing adenosine triphosphate (ATP)-powered ion pumps (which provide energy for cells) was used as a source of ions (which were converted to electrons to power the chip).

The study, led by Ken Shepard, Lau Family Professor of Electrical Engineering and professor of biomedical engineering at Columbia Engineering, was published online today (Dec. 7, 2015) in an open-access paper in Nature Communications.

How to build a hybrid biochip

Living systems achieve this functionality with their own version of electronics based on lipid membranes and ion channels and pumps, which act as a kind of “biological transistor.” Charge in the form of ions carry energy and information, and ion channels control the flow of ions across cell membranes.

Solid-state systems, such as those in computers and communication devices, use electrons; their electronic signaling and power are controlled by field-effect transistors.

To build a prototype of their hybrid system, Shepard’s team packaged a CMOS integrated circuit (IC) with an ATP-harvesting “biocell.” In the presence of ATP, the system pumped ions across the membrane, producing an electrical potential (voltage)* that was harvested by the integrated circuit.

“We made a macroscale version of this system, at the scale of several millimeters, to see if it worked,” Shepard notes. “Our results provide new insight into a generalized circuit model, enabling us to determine the conditions to maximize the efficiency of harnessing chemical energy through the action of these ion pumps. We will now be looking at how to scale the system down.”

While other groups have harvested energy from living systems, Shepard and his team are exploring how to do this at the molecular level, isolating just the desired function and interfacing this with electronics. “We don’t need the whole cell,” he explains. “We just grab the component of the cell that’s doing what we want. For this project, we isolated the ATPases because they were the proteins that allowed us to extract energy from ATP.”

The capability of a bomb-sniffing dog, no Alpo required

Next, the researchers plan to go much further, such as recognizing specific molecules and giving chips the potential to taste and smell.

The ability to build a system that combines the power of solid-state electronics with the capabilities of biological components has great promise, they believe. “You need a bomb-sniffing dog now, but if you can take just the part of the dog that is useful — the molecules that are doing the sensing — we wouldn’t need the whole animal,” says Shepard.

The technology could also provide a power source for implanted electronic devices in ATP-rich environments such as inside living cells, the researchers suggest.

*  “In general, integrated circuits, even when operated at the point of minimum energy in subthreshold, consume on the order of 10⁻² W mm⁻² (or assuming a typical silicon chip thickness of 250 μm, 4 × 10⁻² W mm⁻³). Typical cells, in contrast, consume on the order of 4 × 10⁻⁶ W mm⁻³. In the experiment, a typical active power dissipation for the IC circuit was 92.3 nW, and the active average harvesting power was 71.4 fW for the biocell (the discrepancy is managed through duty-cycled operation of the IC).” — Jared M. Roseman et al./Nature Communications

 

references:

Jared M. Roseman et al. Hybrid integrated biological–solid-state system powered with adenosine triphosphate. Nature Communications 6, 10070 doi:10.1038/ncomms10070. 07 December 2015 (open access)

Topics: Biotech | Electronics | Synthetic Biology

Hybrid integrated biological–solid-state system powered with adenosine triphosphate

Jared M. Roseman, Jianxun Lin, Siddharth Ramakrishnan, Jacob K. Rosenstein & Kenneth L. Shepard
Nature Communications 7 Dec 2015; 6(10070)     http://dx.doi.org:/10.1038/ncomms10070

There is enormous potential in combining the capabilities of the biological and the solid state to create hybrid engineered systems. While there have been recent efforts to harness power from naturally occurring potentials in living systems in plants and animals to power complementary metal-oxide-semiconductor integrated circuits, here we report the first successful effort to isolate the energetics of an electrogenic ion pump in an engineered in vitro environment to power such an artificial system. An integrated circuit is powered by adenosine triphosphate through the action of Na⁺/K⁺ adenosine triphosphatases in an integrated in vitro lipid bilayer membrane. The ion pumps (active in the membrane at numbers exceeding 2 × 10⁶ mm⁻²) are able to sustain a short-circuit current of 32.6 pA mm⁻² and an open-circuit voltage of 78 mV, providing for a maximum power transfer of 1.27 pW mm⁻² from a single bilayer. Two series-stacked bilayers provide a voltage sufficient to operate an integrated circuit with a conversion efficiency of chemical to electrical energy of 14.9%.

 

Figure 1: Fully hybrid biological–solid-state system.

 

 

http://www.nature.com/ncomms/2015/151207/ncomms10070/images/ncomms10070-f1.jpg

(a) Illustration depicting biocell attached to CMOS integrated circuit. (b) Illustration of membrane in pore containing sodium–potassium pumps. (c) Circuit model of equivalent stacked membranes, =2.1 pA, =98.6 GΩ, =575 GΩ and =75 pF, Ag/AgCl electrode equivalent resistance R_WE+R_CE<20 kΩ, energy-harvesting capacitor C_STOR=100 nF combined with switch as an impedance transformation network (only one switch necessary due to small duty cycle), and CMOS IC voltage doubler and resistor representing digital switching load. R_L represents the four independent ring oscillator loads. (d) Equivalent circuit detail of stacked biocell. (e) Switched-capacitor voltage doubler circuit schematic.

 

The energetics of living systems are based on electrochemical membrane potentials that are present in cell plasma membranes, the inner membrane of mitochondria, or the thylakoid membrane of chloroplasts¹. In the latter two cases, the specific membrane potential is known as the proton-motive force and is used by proton adenosine triphosphate (ATP) synthases to produce ATP. In the former case, Na⁺/K⁺-ATPases hydrolyse ATP to maintain the resting potential in most cells.

While there have been recent efforts to harness power from some naturally occurring potentials in living systems that are the result of ion pump action both in plants² and animals^{3, 4} to power complementary metal-oxide semiconductor (CMOS) integrated circuits (ICs), this work is the first successful effort to isolate the energetics of an electrogenic ion pump in an engineered in vitroenvironment to power such an artificial system. Prior efforts to harness power from in vitromembrane systems incorporating ion-pumping ATPases^{5, 6, 7, 8, 9} and light-activated bacteriorhodopsin^{9, 10, 11} have been limited by difficulty in incorporating these proteins in sufficient quantity to attain measurable current and in achieving sufficiently large membrane resistances to harness these currents. Both problems are solved in this effort to power an IC from ATP in an in vitro environment. The resulting measurements provide new insight into a generalized circuit model, which allows us to determine the conditions to maximize the efficiency of harnessing chemical energy through the action of electrogenic ion pumps.

 

ATP-powered IC

Figure 1a shows the complete hybrid integrated system, consisting of a CMOS IC packaged with an ATP-harvesting ‘biocell’. The biocell consists of two series-stacked ATPase bearing suspended lipid bilayers with a fluid chamber directly on top of the IC. Series stacking of two membranes is necessary to provide the required start-up voltage for IC and eliminates the need for an external energy source, which is typically required to start circuits from low-voltage supplies^{2, 3}. As shown inFig. 1c, a matching network in the form of a switched capacitor allows the load resistance of the IC to be matched to that presented by the biocell. In principle, the switch S can be implicit. The biocell charges C_STOR until the self start-up voltage, V_start, is reached. The chip then operates until the biocell voltage drops below the minimum supply voltage for operation, V_min. Active current draw from the IC stops at this point, allowing the charge to build up again on C_STOR. In our case, however, the IC leakage current exceeds 13.5 nA at V_start, more than can be provided by the biocell. As a result, an explicit transistor switch and comparator (outside of the IC) are used for this function in the experimental results presented here, which are not powered by the biocell and not included in energy efficiency calculations (see Supplementary Discussion for additional details). The energy from the biocell is used to operate a voltage converter (voltage doubler) and some simple inverter-based ring oscillators in the IC, which receive power from no other sources.

http://www.nature.com/ncomms/2015/151207/ncomms10070/images/ncomms10070-f1.jpg

 

……..   Prior to the addition of ATP, the membrane produces no electrical power and has an R_m of 280 GΩ. A 1.7-pA short-circuit (SC) current (Fig. 2b) through the membrane is observed upon the addition of ATP (final concentration 3 mM) to the cis chamber where functional, properly oriented enzymes generate a net electrogenic pump current. To perform these measurements, currents through each membrane of the biocell are measured using a voltage-clamp amplifier (inset of Fig. 2b) with a gain of 500 GΩ with special efforts taken to compensate amplifier leakage currents. Each ATPase transports three Na⁺ ions from the cis chamber to the trans chamber and two K⁺ ions from thetrans chamber to the cis chamber (a net charge movement of one cation) for every molecule of ATP hydrolysed. At a rate of 100 hydrolysis events per second under zero electrical (SC) bias¹³, this results in an electrogenic current of ~16 aA. The observed SC current corresponds to about 10⁵ active ATPases in the membrane or a concentration of about 2 × 10⁶ mm⁻², about 5% of the density of channels occurring naturally in mammalian nerve fibres¹⁴. It is expected that half of the channels inserted are inactive because they are oriented incorrectly.

Figure 2: Single-cell biocell characterization.

http://www.nature.com/ncomms/2015/151207/ncomms10070/images_article/ncomms10070-f2.jpg

(a)…Pre-ATP data linear fit (black line) slope yield R_m=280 GΩ. Post ATP data fit to a Boltzmann curve, slope=0.02 V (blue line). Post-ATP linear fit (red line) yields I_p=−1.8 pA and R_p=61.6 GΩ, which corresponds to a per-ATP source resistance of 6.16 × 10¹⁵. The current due to membrane leakage through R_{m} is subtracted in the post-ATP curve…. (b)…

 

Current–voltage characteristics of the ATPases

Figure 2a shows the complete measured current–voltage (I–V) characteristic of a single ATPase-bearing membrane in the presence of ATP. The current due to membrane leakage through R_m is subtracted in the post-ATP curve. The I–V characteristic fits a Boltzmann sigmoid curve, consistent with sodium–potassium pump currents measured on membrane patches at similar buffer conditions^{13, 15, 16}. This nonlinear behaviour reflects the fact that the full ATPase transport cycle (three Na⁺ ions from cis to trans and two K⁺ ions from trans to cis) time increases (the turn-over rate, k_ATP, decreases) as the membrane potential increases¹⁶. No effect on pump current is expected from any ion concentration gradients produced by the action of the ATPases (seeSupplementary Discussion). Using this Boltzmann fit, we can model the biocell as a nonlinear voltage-controlled current source I_ATPase (inset Fig. 2a), in which the current produced by this source varies as a function of V_m. In the fourth quadrant, where the cell is producing electrical power, this model can be linearized as a Norton equivalent circuit, consisting of a DC current source (I_p) in parallel with a current-limiting resistor (R_p), which acts to limit the current delivered to the load at increasing bias (I_ATPase~I_p−V_m/R_p). Figure 2c shows the measured and simulated charging of C_m for a single membrane (open-circuited voltage). A custom amplifier with input resistance R_in>10 TΩ was required for this measurement (see Electrical Measurement Methods).

 

Reconciling operating voltage differences

The electrical characteristics of biological systems and solid-state systems are mismatched in their operating voltages. The minimum operating voltage of solid-state systems is determined by the need for transistors to modulate a Maxwell–Boltzmann (MB) distribution of carriers by several orders of magnitude through the application of a potential that is several multiples of kT/q (where kis Boltzmann’s constant, T is the temperature in degrees Kelvin and q is the elementary charge). Biological systems, while operating under the same MB statistics, have no such constraints for operating ion channels since they are controlled by mechanical (or other conformational) processes rather than through modulation of a potential barrier. To bridge this operating voltage mismatch, the circuit includes a switched-capacitor voltage doubler (Fig. 1d) that is capable of self-startup from voltages as low V_start=145 mV (~5.5 kT/q) and can be operated continuously from input voltages from as low as V_min=110 mV (see Supplementary Discussion)…..

 

Maximizing the efficiency of harvesting energy from ATP

Solid-state systems and biological systems are also mismatched in their operating impedances. In our case, the biocell presents a source impedance, =84.2 GΩ, while the load impedance presented by the complete integrated circuit (including both the voltage converter and ring oscillator loads) is approximately R_IC=200 kΩ. (The load impedance, R_L, of the ring oscillators alone is 305 kΩ.) This mismatch in source and load impedance is manifest in large differences in power densities. In general, integrated circuits, even when operated at the point of minimum energy in subthreshold, consume on the order of 10⁻² W mm⁻² (or assuming a typical silicon chip thickness of 250 μm, 4 × 10⁻² W mm⁻³) (ref. 17). Typical cells, in contrast, consume on the order of 4 × 10⁻⁶ W mm⁻³ (ref. 18). In our case, a typical active power dissipation for our circuit is 92.3 nW, and the active average harvesting power is 71.4 fW for the biocell. This discrepancy is managed through duty-cycled operation of the IC in which the circuit is largely disabled for long periods of time (T_charge), integrating up the power onto a storage capacitor (C_STOR), which is then expended in a very brief period of activity (T_run), as shown in Fig. 3a.

The overall efficiency of the system in converting chemical energy to the energy consumed in the load ring oscillator (η) is given by the product of the conversion efficiency of the voltage doubler (η_converter) and the conversion efficiency of chemical energy to electrical energy in the biocell (η_biocell), η=η_converter × η_biocell. η_converter is relatively constant over the range of input voltages at ~59%, as determined by various loading test circuits included in the chip design (Supplementary Figs 1–6). η_biocell, however, varies with transmembrane potential V_m. η is the efficiency in transferring power to the power ring oscillator loads from the ATP harvested by biocell.

…….

To first order, the energy made available to the Na⁺/K⁺-ATPase by the hydrolysis of ATP is independent of the chemical or electric potential of the membrane and is given by |ΔG_ATP|/(qN_A), where ΔG_ATP is the Gibbs free energy change due to the ATP hydrolysis reaction per mole of ATP at given buffer conditions and N_A is Avogadro’s number. Since every charge that passes through I_ATPase corresponds to a single hydrolysis event, we can use two voltage sources in series with I_ATPase to independently account for the energy expended by the pumps both in moving charge across the electric potential difference and in moving ions across the chemical potential difference. The dependent voltage source V_loss in this branch fixes the voltage across I_ATPase, and the total power produced by the pump current source is (|ΔG_ATP|/N_A)(Nk_ATP), which is the product of the energy released per molecule of ATP, the number of active ATPases and the ATP turnover rate. The power dissipated in voltage source V_chem models the work performed by the ATPases in transporting ions against a concentration gradient. In the case of the Na⁺/K⁺ ATPase,V_chem is given by . The power dissipated in this source is introduced back into the circuit in the power generated by the Nernst independent voltage sources, and . The power dissipated in the dependent voltage source V_loss models any additional power not used to perform chemical or electrical work. ……

 

Integration of ATP-harvesting ion pumps could provide a means to power future CMOS microsystems scaled to the level of individual cells²². In molecular diagnostics, the integration of pore-forming proteins such as alpha haemolysin²³ or MspA porin²⁴ with CMOS electronics is already finding application in DNA sequencing²⁵. Exploiting the large diversity of function available in transmembrane proteins in these hybrid systems could, for example, lead to highly specific sensing platforms for airborne odorants or soluble molecular entities^{26, 27}. Heavily multiplexed platforms could become high-throughput in vitro drug-screening platforms against this diversity of function. In addition, integration of transmembrane proteins with CMOS may become a convenient alternative to fluorescence for coupling to synthetic biological systems²⁸.

 

Roseman, J. M. et al. Hybrid integrated biological–solid-state system powered with adenosine triphosphate. Nat. Commun. 6:10070      http://dx.doi.org:/10.1038/ncomms10070 (2015).

 

 

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Topology of Protein Complexes

Posted in Physics, Proteins, Proteomics, Sensors & Analytics, Signaling, Translational Science, Unfolded Protein Response (UPR), tagged classification of protein assemblies, Inflammasome, mRNA, protein, protein-protein interactions, tertiary structure, transcription on December 11, 2015| Leave a Comment »

Topology of Protein Complexes

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Periodic Table of Protein Complexes Unveiled

http://www.genengnews.com/gen-news-highlights/periodic-table-of-protein-complexes-unveiled/81252091/

 

 

http://www.genengnews.com/Media/images/GENHighlight/thumb_Dec11_2015_EMBLEBI_ProteinComplexesPeriodicTable1692141643.jpg

A new periodic table presents a systematic, ordered view of protein assembly, providing a visual tool for understanding biological function. [EMBL-EBI / Spencer Phillips]

 

Move over Mendeleev, there’s a new periodic table in science. Unlike the original periodic table, which organized the chemical elements, the new periodic table organizes protein complexes, or more precisely, quaternary structure topologies. Though there are other differences between the old and new periodic tables, they share at least one important feature—predictive power.

When Mendeleev introduced his periodic table, he predicted that when new chemical elements were discovered, they would fill his table’s blank spots. Analogous predictions are being ventured by the scientific team that assembled the new periodic table. This team, consisting of scientists from the Wellcome Genome Campus and the University of Cambridge, asserts that its periodic table reveals the regions of quaternary structure space that remain to be populated.

The periodic table of protein complexes not only offers a new way of looking at the enormous variety of structures that proteins can build in nature, it also indicates which structures might be discovered next. Moreover, it could point protein engineers toward entirely novel structures that never occurred in nature, but could be engineered.

The new table appeared December 11 in the journal Science, in an article entitled, “Principles of assembly reveal a periodic table of protein complexes.” The “principles of assembly” referenced in this title amount to three basic assembly types: dimerization, cyclization, and heteromeric subunit addition. In dimerization, one protein complex subunit doubles, and becomes two; in cyclization, protein complex subunits from a ring of three or more; and in heteromeric subunit addition, two different proteins bind to each other.

These steps, repeated in different combinations, gives rise to enormous number of proteins of different kinds. “Evolution has given rise to a huge variety of protein complexes, and it can seem a bit chaotic,” explained Joe Marsh, Ph.D., formerly of the Wellcome Genome Campus and now of the MRC Human Genetics Unit at the University of Edinburgh. “But if you break down the steps proteins take to become complexes, there are some basic rules that can explain almost all of the assemblies people have observed so far.”

The authors of the Science article noted that many protein complexes assemble spontaneously via ordered pathways in vitro, and these pathways have a strong tendency to be evolutionarily conserved. “[There] are strong similarities,” the authors added, “between protein complex assembly and evolutionary pathways, with assembly pathways often being reflective of evolutionary histories, and vice versa. This suggests that it may be useful to consider the types of protein complexes that have evolved from the perspective of what assembly pathways are possible.”

To explore this rationale, the authors examined the fundamental steps by which protein complexes can assemble, using electrospray mass spectrometry experiments, literature-curated assembly data, and a large-scale analysis of protein complex structures. Ultimately, they derived their approach to explaining the observed distribution of known protein complexes in quaternary structure space. This approach, they insist, provides a framework for understanding their evolution.

“In addition, it can contribute considerably to the prediction and modeling of quaternary structures by specifying which topologies are most likely to be adopted by a complex with a given stoichiometry, potentially providing constraints for multi-subunit docking and hybrid methods,” the authors concluded. “Lastly, it could help in the bioengineering of protein complexes by identifying which topologies are most likely to be stable, and thus which types of essential interfaces need to be engineered.”

The rows and columns of the periodic table of the elements, called periods and groups, were originally determined by each element’s atomic mass and chemical properties, later by atomic number and electron configuration. In contrast, the rows and columns of the periodic table of protein complexes correspond to the number of different subunit types and the number of times these subunits are repeated. The new table is not, it should be noted, periodic in the same sense as the periodic table of the elements. It is in principle open-ended.

Although there are no theoretical limitations to quaternary structure topology space in either dimension, the abridged version of the table presented in the Science article can accommodate the vast majority of known structures. Moreover, when the table’s creators compared the large variety of countenanced topologies to observed structures, they found that about 92% of known protein complex structures were compatible with their model.

“Despite its strong predictive power, the basic periodic table model does not account for about 8% of known protein complex structures,” the authors conceded. “More than half of these exceptions arise as a result of quaternary structure assignment errors.

“A benefit of this approach is that it highlights likely quaternary structure misassignments, particularly by identifying nonbijective complexes with even subunit stoichiometry. However, this still leaves about 4% of known structures that are correct but are not compatible with the periodic table.” The authors added that the exceptions to their model are interesting in their own right, and are the subject of ongoing studies.

 

 

http://phys.org/news/2015-12-periodic-table-protein-complexes.html

The Periodic Table of Protein Complexes, published today in Science, offers a new way of looking at the enormous variety of structures that proteins can build in nature, which ones might be discovered next, and predicting how entirely novel structures could be engineered. Created by an interdisciplinary team led by researchers at the Wellcome Genome Campus and the University of Cambridge, the Table provides a valuable tool for research into evolution and protein engineering.

Different ballroom dances can be seen as an endless combination of a small number of basic steps. Similarly, the ‘dance’ of protein complex assembly can be seen as endless variations on dimerization (one doubles, and becomes two), cyclisation (one forms a ring of three or more) and subunit addition (two different proteins bind to each other). Because these happen in a fairly predictable way, it’s not as hard as you might think to predict how a novel protein would form.

“We’re bringing a lot of order into the messy world of protein complexes,” explains Sebastian Ahnert of the Cavendish Laboratory at the University of Cambridge, a physicist who regularly tangles with biological problems. “Proteins can keep go through several iterations of these simple steps, , adding more and more levels of complexity and resulting in a huge variety of structures. What we’ve made is a classification based on these underlying principles that helps people get a handle on the complexity.”

The exceptions to the rule are interesting in their own right, adds Sebastian, as are the subject of on-going studies.

“By analysing the tens of thousands of protein complexes for which three-dimensional structures have already been experimentally determined, we could see repeating patterns in the assembly transitions that occur – and with new data from mass spectrometry we could start to see the bigger picture,” says Joe.

“The core work for this study is in theoretical physics and computational biology, but it couldn’t have been done without the mass spectrometry work by our colleagues at Oxford University,” adds Sarah Teichmann, Research Group Leader at the European Bioinformatics Institute (EMBL-EBI) and the Wellcome Trust Sanger Institute. “This is yet another excellent example of how extremely valuable interdisciplinary research can be.”

Read more at: http://phys.org/news/2015-12-periodic-table-protein-complexes.html#jCp

 

More information: “Principles of assembly reveal a periodic table of protein complexes” www.sciencemag.org/lookup/doi/10.1126/science.aaa2245

PRINCIPLES OF ASSEMBLY REVEAL A PERIODIC TABLE OF PROTEIN COMPLEXES

Sebastian E. Ahnert¹,*, Joseph A. Marsh²,³,*, Helena Hernández⁴, Carol V. Robinson⁴, Sarah A. Teichmann¹,³,⁵,†
Science 11 Dec 2015; 350(6266): aaa2245         DOI:http://dx.doi.org:/10.1126/science.aaa2245      

INTRODUCTION

The assembly of proteins into complexes is crucial for most biological processes. The three-dimensional structures of many thousands of homomeric and heteromeric protein complexes have now been determined, and this has had a broad impact on our understanding of biological function and evolution. Despite this, the organizing principles that underlie the great diversity of protein quaternary structures observed in nature remain poorly understood, particularly in comparison with protein folds, which have been extensively classified in terms of their architecture and evolutionary relationships.

RATIONALE

In this work, we sought a comprehensive understanding of the general principles underlying quaternary structure organization. Our approach was to consider protein complexes in terms of their assembly. Many protein complexes assemble spontaneously via ordered pathways in vitro, and these pathways have a strong tendency to be evolutionarily conserved. Furthermore, there are strong similarities between protein complex assembly and evolutionary pathways, with assembly pathways often being reflective of evolutionary histories, and vice versa. This suggests that it may be useful to consider the types of protein complexes that have evolved from the perspective of what assembly pathways are possible.

RESULTS

We first examined the fundamental steps by which protein complexes can assemble, using electrospray mass spectrometry experiments, literature-curated assembly data, and a large-scale analysis of protein complex structures. We found that most assembly steps can be classified into three basic types: dimerization, cyclization, and heteromeric subunit addition. By systematically combining different assembly steps in different ways, we were able to enumerate a large set of possible quaternary structure topologies, or patterns of key interfaces between the proteins within a complex. The vast majority of real protein complex structures lie within these topologies. This enables a natural organization of protein complexes into a “periodic table,” because each heteromer can be related to a simpler symmetric homomer topology. Exceptions are mostly the result of quaternary structure assignment errors, or cases where sequence-identical subunits can have different interactions and thus introduce asymmetry. Many of these asymmetric complexes fit the paradigm of a periodic table when their assembly role is considered. Finally, we implemented a model based on the periodic table, which predicts the expected frequencies of each quaternary structure topology, including those not yet observed. Our model correctly predicts quaternary structure topologies of recent crystal and electron microscopy structures that are not included in our original data set.

CONCLUSION

This work explains much of the observed distribution of known protein complexes in quaternary structure space and provides a framework for understanding their evolution. In addition, it can contribute considerably to the prediction and modeling of quaternary structures by specifying which topologies are most likely to be adopted by a complex with a given stoichiometry, potentially providing constraints for multi-subunit docking and hybrid methods. Lastly, it could help in the bioengineering of protein complexes by identifying which topologies are most likely to be stable, and thus which types of essential interfaces need to be engineered.

http://www.sciencemag.org/content/350/6266/aaa2245/F1.small.gif

Protein assembly steps lead to a periodic table of protein complexes and can predict likely quaternary structure topologies.

Three main assembly steps are possible: cyclization, dimerization, and subunit addition. By combining these in different ways, a large set of possible quaternary structure topologies can be generated. These can be arranged on a periodic table that describes most known complexes and that can predict previously unobserved topologies.

Ahnert SE, et. al. ‘Principles of assembly reveal a periodic table of protein complexes.’
Science (2015).   DOI: http://dx.doi.org:/10.1126/science.aaa2245    http://www.cam.ac.uk/research/news/the-periodic-table-of-proteins

 

Evolution, classification and dynamics of protein complexes

• Sarah Teichmann
• Thursday 15 October 2015, 12:00–13:00
• TCM Seminar room, 530 Mott building.

This talk is included in these lists:

• Biological and Statistical Physics discussion group (BSDG)
• Combined TCM Seminars and TCM blackboard seminar listing
• PMRFPS’s
• TCM Seminar room, 530 Mott building

This talk is part of the Biological and Statistical Physics discussion group (BSDG) series.

Classification of protein structure has had a broad impact on our understanding of biological function and evolution, yet this work has largely focused on individual protein domains and their pairwise interactions. In contrast, the assembly of individual polypeptides into protein complexes, which are ubiquitous in cells, has received comparatively little attention. The periodic table of protein complexes is a new framework for analysis of complexes based on the principles of self-assembly. This reveals that sequence-identical subunits almost always have identical assembly roles within a complex and allows us to unify the vast majority of complexes of known structure (~32,000) into about 120 topologies. This facilitates the exhaustive enumeration of unobserved protein complex topologies and has significant practical applications for quaternary structure prediction, modelling and engineering.

http://talks.cam.ac.uk/talk/index/61632

 

 

Genome-wide analysis of thylakoid-bound ribosomes in maize reveals principles of cotranslational targeting to the thylakoid membrane

Reimo Zoschke1 and Alice Barkan2
http://www.pnas.org/content/112/13/E1678.full.pdf

Chloroplast genomes encode ∼37 proteins that integrate into the thylakoid membrane. The mechanisms that target these proteins to the membrane are largely unexplored. We used ribosome profiling to provide a comprehensive, high-resolution map of ribosome positions on chloroplast mRNAs in separated membrane and soluble fractions in maize seedlings. The results show that translation invariably initiates off the thylakoid membrane and that ribosomes synthesizing a subset of membrane proteins subsequently become attached to the membrane in a nucleaseresistant fashion. The transition from soluble to membraneattached ribosomes occurs shortly after the first transmembrane segment in the nascent peptide has emerged from the ribosome. Membrane proteins whose translation terminates before emergence of a transmembrane segment are translated in the stroma and targeted to the membrane posttranslationally. These results indicate that the first transmembrane segment generally comprises the signal that links ribosomes to thylakoid membranes for cotranslational integration. The sole exception is cytochrome f, whose cleavable N-terminal cpSecA-dependent signal sequence engages the thylakoid membrane cotranslationally. The distinct behavior of ribosomes synthesizing the inner envelope protein CemA indicates that sorting signals for the thylakoid and envelope membranes are distinguished cotranslationally. In addition, the fractionation behavior of ribosomes in polycistronic transcription units encoding both membrane and soluble proteins adds to the evidence that the removal of upstream ORFs by RNA processing is not typically required for the translation of internal genes in polycistronic chloroplast mRNAs.

 

Significance Proteins in the chloroplast thylakoid membrane system are derived from both the nuclear and plastid genomes. Mechanisms that localize nucleus-encoded proteins to the thylakoid membrane have been studied intensively, but little is known about the analogous issues for plastid-encoded proteins. This genome-wide, high-resolution analysis of the partitioning of chloroplast ribosomes between membrane and soluble fractions revealed that approximately half of the chloroplast encoded thylakoid proteins integrate cotranslationally and half integrate posttranslationally. Features in the nascent peptide that underlie these distinct behaviors were revealed by analysis of the position on each mRNA at which elongating ribosomes first become attached to the membrane.

 

 

Structures of the HIN Domain:DNA Complexes Reveal Ligand Binding and Activation Mechanisms of the AIM2 Inflammasome and IFI16 Receptor

Tengchuan Jin, Andrew Perry, Jiansheng Jiang, Patrick Smith, James A. Curry, et al.
Immunity 20 Apr 2012; 36(4):561–571    http://dx.doi.org/10.1016/j.immuni.2012.02.014

http://www.cell.com/cms/attachment/2007963858/2030721291/fx1.jpg

Highlights

• Electrostatic attraction underlies innate dsDNA recognition by the HIN domains
• Both OB folds and the linker between them engage the dsDNA backbone
• An autoinhibited state of AIM2 is activated by DNA that liberates the PYD domain
• DNA serves as an oligomerization platform for the inflammasome assembly

 

Summary

Recognition of DNA by the innate immune system is central to antiviral and antibacterial defenses, as well as an important contributor to autoimmune diseases involving self DNA. AIM2 (absent in melanoma 2) and IFI16 (interferon-inducible protein 16) have been identified as DNA receptors that induce inflammasome formation and interferon production, respectively. Here we present the crystal structures of their HIN domains in complex with double-stranded (ds) DNA. Non-sequence-specific DNA recognition is accomplished through electrostatic attraction between the positively charged HIN domain residues and the dsDNA sugar-phosphate backbone. An intramolecular complex of the AIM2 Pyrin and HIN domains in an autoinhibited state is liberated by DNA binding, which may facilitate the assembly of inflammasomes along the DNA staircase. These findings provide mechanistic insights into dsDNA as the activation trigger and oligomerization platform for the assembly of large innate signaling complexes such as the inflammasomes.

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Biochemistry and Dysmetabolism of Aging and Serious Illness

Posted in Alzheimer's Disease, Amino acids, Biochemical pathways, Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiomyopathy, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Cognition, Computational Biology/Systems and Bioinformatics, Curation, DNA repair, Fatty acids, Frontiers in Cardiology and Cardiovascular Disorders, Gene Regulation, Genome Biology, Hematology, Hematopoiesis, Human aging, Kinase, Lipid metabolism, Metabolism, Neurodegenerative Diseases, Oxidative phosphorylation, Proteins, Proteomics, Schizophrenia, Signaling, Signaling & Cell Circuits, Warburg effect, tagged Cancer - General, IGF1, Insulin, mitochondria, Oxidative phosphorylation, skeletal and cardiomyocyte on November 19, 2015| Leave a Comment »

Biochemistry and Dysmetabolism of Aging and Serious Illness

Curator: Larry H. Bernstein, MD, FCAP

 

White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer’s Disease

Lauren P. Klosinski, Jia Yao, Fei Yin, Alfred N. Fonteh, Michael G. Harrington, Trace A. Christensen, Eugenia Trushina, Roberta Diaz Brinton
http://www.ebiomedicine.com/article/S2352-3964(15)30192-4/abstract      DOI: http://dx.doi.org/10.1016/j.ebiom.2015.11.002

Highlights

• •Mitochondrial dysfunction activates mechanisms for catabolism of myelin lipids to generate ketone bodies for ATP production.
• •Mechanisms leading to ketone body driven energy production in brain coincide with stages of reproductive aging in females.
• •Sequential activation of myelin catabolism pathway during aging provides multiple therapeutic targets and windows of efficacy.

The mechanisms underlying white matter degeneration, a hallmark of multiple neurodegenerative diseases including Alzheimer’s, remain unclear. Herein we provide a mechanistic pathway, spanning multiple transitions of aging, that links mitochondrial dysfunction early in aging with later age white matter degeneration. Catabolism of myelin lipids to generate ketone bodies can be viewed as an adaptive survival response to address brain fuel and energy demand. Women are at greatest risk of late-onset-AD, thus, our analyses in female brain address mechanisms of AD pathology and therapeutic targets to prevent, delay and treat AD in the sex most affected with potential relevance to men.

 

White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer’s. Age remains the greatest risk factor for Alzheimer’s and the prevalence of age-related late onset Alzheimer’s is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer’s risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A₂ sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer’s and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical.

3. Results

1. 3.1. Pathway of Mitochondrial Deficits, H2O2 Production and cPLA2 Activation in the Aging Female Brain
2. 3.2. cPLA2-sphingomyelinase Pathway Activation in White Matter Astrocytes During Reproductive Senescence
3. 3.3. Investigation of White Matter Gene Expression Profile During Reproductive Senescence
4. 3.4. Ultra Structural Analysis of Myelin Sheath During Reproductive Senescence
5. 3.5. Analysis of the Lipid Profile of Brain During the Transition to Reproductive Senescence
6. 3.6. Fatty Acid Metabolism and Ketone Generation Following the Transition to Reproductive Senescence

 

4. Discussion

Age remains the greatest risk factor for developing AD (Hansson et al., 2006, Alzheimer’s, 2015). Thus, investigation of transitions in the aging brain is a reasoned strategy for elucidating mechanisms and pathways of vulnerability for developing AD. Aging, while typically perceived as a linear process, is likely composed of dynamic transition states, which can protect against or exacerbate vulnerability to AD (Brinton et al., 2015). An aging transition unique to the female is the perimenopausal to menopausal conversion (Brinton et al., 2015). The bioenergetic similarities between the menopausal transition in women and the early appearance of hypometabolism in persons at risk for AD make the aging female a rational model to investigate mechanisms underlying risk of late onset AD.

Findings from this study replicate our earlier findings that age of reproductive senescence is associated with decline in mitochondrial respiration, increased H₂O₂ production and shift to ketogenic metabolism in brain (Yao et al., 2010, Ding et al., 2013, Yin et al., 2015). These well established early age-related changes in mitochondrial function and shift to ketone body utilization in brain, are now linked to a mechanistic pathway that connects early decline in mitochondrial respiration and H₂O₂ production to activation of the cPLA₂-sphingomyelinase pathway to catabolize myelin lipids resulting in WM degeneration (Fig. 12). These lipids are sequestered in lipid droplets for subsequent use as a local source of ketone body generation via astrocyte mediated beta-oxidation of fatty acids. Astrocyte derived ketone bodies can then be transported to neurons where they undergo ketolysis to generate acetyl-CoA for TCA derived ATP generation required for synaptic and cell function (Fig. 12).

http://www.ebiomedicine.com/cms/attachment/2040395791/2053874721/gr12.sml

Fig. 12

Schematic model of mitochondrial H₂O₂ activation of cPLA₂-sphingomyelinase pathway as an adaptive response to provide myelin derived fatty acids as a substrate for ketone body generation: The cPLA₂-sphingomyelinase pathway is proposed as a mechanistic pathway that links an early event, mitochondrial dysfunction and H₂O₂, in the prodromal/preclinical phase of Alzheimer’s with later stage development of pathology, white matter degeneration. Our findings demonstrate that an age dependent deficit in mitochondrial respiration and a concomitant rise in oxidative stress activate an adaptive cPLA₂-sphingomyelinase pathway to provide myelin derived fatty acids as a substrate for ketone body generation to fuel an energetically compromised brain.

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Biochemical evidence obtained from isolated whole brain mitochondria confirms that during reproductive senescence and in response to estrogen deprivation brain mitochondria decline in respiratory capacity (Yao et al., 2009, Yao et al., 2010, Brinton, 2008a, Brinton, 2008b, Swerdlow and Khan, 2009). A well-documented consequence of mitochondrial dysfunction is increased production of reactive oxygen species (ROS), specifically H₂O₂ (Boveris and Chance, 1973, Beal, 2005, Yin et al., 2014, Yap et al., 2009). While most research focuses on the damage generated by free radicals, in this case H₂O₂ functions as a signaling molecule to activate cPLA₂, the initiating enzyme in the cPLA₂-sphingomyelinase pathway (Farooqui and Horrocks, 2006, Han et al., 2003, Sun et al., 2004). In AD brain, increased cPLA₂ immunoreactivity is detected almost exclusively in astrocytes suggesting that activation of the cPLA₂-sphingomyelinase pathway is localized to astrocytes in AD, as opposed to the neuronal or oligodendroglial localization that is observed during apoptosis (Sun et al., 2004, Malaplate-Armand et al., 2006, Di Paolo and Kim, 2011, Stephenson et al., 1996,Stephenson et al., 1999). In our analysis, cPLA₂ (Sanchez-Mejia and Mucke, 2010) activation followed the age-dependent rise in H₂O₂ production and was sustained at an elevated level.

Direct and robust activation of astrocytic cPLA₂ by physiologically relevant concentrations of H₂O₂ was confirmed in vitro. Astrocytic involvement in the cPLA₂-sphingomyelinase pathway was also indicated by an increase in cPLA₂ positive astrocyte reactivity in WM tracts of reproductively incompetent mice. These data are consistent with findings from brains of persons with AD that demonstrate the same striking localization of cPLA₂immunoreactivity within astrocytes, specifically in the hippocampal formation (Farooqui and Horrocks, 2004). While neurons and astrocytes contain endogenous levels of cPLA₂, neuronal cPLA₂ is activated by an influx of intracellular calcium, whereas astrocytic cPLA₂ is directly activated by excessive generation of H₂O₂ (Sun et al., 2004, Xu et al., 2003, Tournier et al., 1997). Evidence of this cell type specific activation was confirmed by the activation of cPLA₂ in astrocytes by H₂O₂ and the lack of activation in neurons. These data support that astrocytic, not neuronal, cPLA₂ is the cellular mediator of the H₂O₂ dependent cPLA₂-sphingomyelinase pathway activation and provide associative evidence supporting a role of astrocytic mitochondrial H₂O₂ in age-related WM catabolism.

The pattern of gene expression during the shift to reproductive senescence in the female mouse hippocampus recapitulates key observations in human AD brain tissue, specifically elevation in cPLA₂, sphingomyelinase and ceramidase (Schaeffer et al., 2010, He et al., 2010, Li et al., 2014). Further, up-regulation of myelin synthesis, lipid metabolism and inflammatory genes in reproductively incompetent female mice is consistent with the gene expression pattern previously reported from aged male rodent hippocampus, aged female non-human primate hippocampus and human AD hippocampus (Blalock et al., 2003, Blalock et al., 2004, Blalock et al., 2010, Blalock et al., 2011, Kadish et al., 2009, Rowe et al., 2007). In these analyses of gene expression in aged male rodent hippocampus, aged female non-human primate hippocampus and human AD hippocampus down regulation of genes related to mitochondrial function, and up-regulation in multiple genes encoding for enzymes involved in ketone body metabolism occurred (Blalock et al., 2003, Blalock et al., 2004, Blalock et al., 2010, Blalock et al., 2011, Kadish et al., 2009, Rowe et al., 2007). The comparability across data derived from aging female mouse hippocampus reported herein and those derived from male rodent brain, female nonhuman brain and human AD brain strongly suggest that cPLA2-sphingomyelinase pathway activation, myelin sheath degeneration and fatty acid metabolism leading to ketone body generation is a metabolic adaptation that is generalizable across these naturally aging models and are evident in aged human AD brain. Collectively, these data support the translational relevance of findings reported herein.

Data obtained via immunohistochemistry, electron microscopy and MBP protein analyses demonstrated an age-related loss in myelin sheath integrity. Evidence for a loss of myelin structural integrity emerged in reproductively incompetent mice following activation of the cPLA₂-sphingomyelinase pathway. The unraveling myelin phenotype observed following reproductive senescence and aging reported herein is consistent with the degenerative phenotype that emerges following exposure to the chemotherapy drug bortezomib which induces mitochondrial dysfunction and increased ROS generation (Carozzi et al., 2010, Cavaletti et al., 2007,Ling et al., 2003). In parallel to the decline in myelin integrity, lipid droplet density increased. In aged mice, accumulation of lipid droplets declined in parallel to the rise in ketone bodies consistent with the utilization of myelin-derived fatty acids to generate ketone bodies. Due to the sequential relationship between WM degeneration and lipid droplet formation, we posit that lipid droplets serve as a temporary storage site for myelin-derived fatty acids prior to undergoing β-oxidation in astrocytes to generate ketone bodies.

Microstructural alterations in myelin integrity were associated with alterations in the lipid profile of brain, indicative of WM degeneration resulting in release of myelin lipids. Sphingomyelin and galactocerebroside are two main lipids that compose the myelin sheath (Baumann and Pham-Dinh, 2001). Ceramide is common to both galactocerebroside and sphingomyelin and is composed of sphingosine coupled to a fatty acid. Ceramide levels increase in aging, in states of ketosis and in neurodegeneration (Filippov et al., 2012, Blazquez et al., 1999, Costantini et al., 2005). Specifically, ceramide levels are elevated at the earliest clinically recognizable stage of AD, indicating a degree of WM degeneration early in disease progression (Di Paolo and Kim, 2011,Han et al., 2002, Costantini et al., 2005). Sphingosine is statistically significantly elevated in the brains of AD patients compared to healthy controls; a rise that was significantly correlated with acid sphingomyelinase activity, Aβ levels and tau hyperphosphorylation (He et al., 2010). In our analyses, a rise in ceramides was first observed early in the aging process in reproductively incompetent mice. The rise in ceramides was coincident with the emergence of loss of myelin integrity consistent with the release of myelin ceramides from sphingomyelin via sphingomyelinase activation. Following the rise in ceramides, sphingosine and fatty acid levels increased. The temporal sequence of the lipid profile was consistent with gene expression indicating activation of ceramidase for catabolism of ceramide into sphingosine and fatty acid during reproductive senescence. Once released from ceramide, fatty acids can be transported into the mitochondrial matrix of astrocytes via CPT-1, where β-oxidation of fatty acids leads to the generation of acetyl-CoA (Glatz et al., 2010). It is well documented that acetyl-CoA cannot cross the inner mitochondrial membrane, thus posing a barrier to direct transport of acetyl-CoA generated by β-oxidation into neurons. In response, the newly generated acetyl-CoA undergoes ketogenesis to generate ketone bodies to fuel energy demands of neurons (Morris, 2005,Guzman and Blazquez, 2004, Stacpoole, 2012). Because astrocytes serve as the primary location of β-oxidation in brain they are critical to maintaining neuronal metabolic viability during periods of reduced glucose utilization (Panov et al., 2014, Ebert et al., 2003, Guzman and Blazquez, 2004).

Once fatty acids are released from myelin ceramides, they are transported into astrocytic mitochondria by CPT1 to undergo β-oxidation. The mitochondrial trifunctional protein HADHA catalyzes the last three steps of mitochondrial β-oxidation of long chain fatty acids, while mitochondrial ABAD (aka SCHAD—short chain fatty acid dehydrogenase) metabolizes short chain fatty acids. Concurrent with the release of myelin fatty acids in aged female mice, CPT1, HADHA and ABAD protein expression as well as ketone body generation increased significantly. These findings indicate that astrocytes play a pivotal role in the response to bioenergetic crisis in brain to activate an adaptive compensatory system that activates catabolism of myelin lipids and the metabolism of those lipids into fatty acids to generate ketone bodies necessary to fuel neuronal demand for acetyl-CoA and ATP.

Collectively, these findings provide a mechanistic pathway that links mitochondrial dysfunction and H₂O₂generation in brain early in the aging process to later stage white matter degeneration. Astrocytes play a pivotal role in providing a mechanistic strategy to address the bioenergetic demand of neurons in the aging female brain. While this pathway is coincident with reproductive aging in the female brain, it is likely to have mechanistic translatability to the aging male brain. Further, the mechanistic link between bioenergetic decline and WM degeneration has potential relevance to other neurological diseases involving white matter in which postmenopausal women are at greater risk, such as multiple sclerosis. The mechanistic pathway reported herein spans time and is characterized by a progression of early adaptive changes in the bioenergetic system of the brain leading to WM degeneration and ketone body production. Translationally, effective therapeutics to prevent, delay and treat WM degeneration during aging and Alzheimer’s disease will need to specifically target stages within the mechanistic pathway described herein. The fundamental initiating event is a bioenergetic switch from being a glucose dependent brain to a glucose and ketone body dependent brain. It remains to be determined whether it is possible to prevent conversion to or reversal of a ketone dependent brain. Effective therapeutic strategies to intervene in this process require biomarkers of bioenergetic phenotype of the brain and stage of mechanistic progression. The mechanistic pathway reported herein may have relevance to other age-related neurodegenerative diseases characterized by white matter degeneration such as multiple sclerosis.

Blood. 2015 Oct 15;126(16):1925-9.    http://dx.doi.org:/10.1182/blood-2014-12-617498. Epub 2015 Aug 14.
Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias.

Ricciardi MR¹, Mirabilii S², Allegretti M², Licchetta R², Calarco A³, Torrisi MR¹, Foà R², Nicolai R⁴, Peluso G³, Tafuri A¹.   Author information

Cancer cells are characterized by perturbations of their metabolic processes. Recent observations demonstrated that the fatty acid oxidation (FAO) pathway may represent an alternative carbon source for anabolic processes in different tumors, therefore appearing particularly promising for therapeutic purposes. Because the carnitine palmitoyl transferase 1a (CPT1a) is a protein that catalyzes the rate-limiting step of FAO, here we investigated the in vitro antileukemic activity of the novel CPT1a inhibitor ST1326 on leukemia cell lines and primary cells obtained from patients with hematologic malignancies. By real-time metabolic analysis, we documented that ST1326 inhibited FAO in leukemia cell lines associated with a dose- and time-dependent cell growth arrest, mitochondrial damage, and apoptosis induction. Data obtained on primary hematopoietic malignant cells confirmed the FAO inhibition and cytotoxic activity of ST1326, particularly on acute myeloid leukemia cells. These data suggest that leukemia treatment may be carried out by targeting metabolic processes.

Oncogene. 2015 Oct 12.   http://dx.doi.org:/10.1038/onc.2015.394. [Epub ahead of print]

Tumour-suppression function of KLF12 through regulation of anoikis.

Godin-Heymann N¹, Brabetz S¹, Murillo MM^1,2, Saponaro M³, Santos CR⁴, Lobley A⁵, East P⁵, Chakravarty P⁵, Matthews N⁶, Kelly G⁵, Jordan S¹, Castellano E¹, Downward J^1,2.  Author information

Suppression of detachment-induced cell death, known as anoikis, is an essential step for cancer metastasis to occur. We report here that expression of KLF12, a member of the Kruppel-like family of transcription factors, is downregulated in lung cancer cell lines that have been selected to grow in the absence of cell adhesion. Knockdown of KLF12 in parental cells results in decreased apoptosis following cell detachment from matrix. KLF12 regulates anoikis by promoting the cell cycle transition through S phase and therefore cell proliferation. Reduced expression levels of KLF12 results in increased ability of lung cancer cells to form tumours in vivo and is associated with poorer survival in lung cancer patients. We therefore identify KLF12 as a novel metastasis-suppressor gene whose loss of function is associated with anoikis resistance through control of the cell cycle.

Mol Cell. 2015 Oct 14. pii: S1097-2765(15)00764-9. doi: 10.1016/j.molcel.2015.09.025. [Epub ahead of print]
PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth.

Montal ED¹, Dewi R², Bhalla K³, Ou L², Hwang BJ², Ropell AE⁴, Gordon C⁴, Liu WJ³, DeBerardinis RJ⁵, Sudderth J⁵, Twaddel W⁶, Boros LG⁷, Shroyer KR⁴,Duraisamy S⁸, Drapkin R⁸, Powers RS⁶, Rohde JM⁹, Boxer MB⁹, Wong KK¹⁰, Girnun GD¹¹.    Author information

Phosphoenolpyruvate carboxykinase (PEPCK) is well known for its role in gluconeogenesis. However, PEPCK is also a key regulator of TCA cycle flux. The TCA cycle integrates glucose, amino acid, and lipid metabolism depending on cellular needs. In addition, biosynthetic pathways crucial to tumor growth require the TCA cycle for the processing of glucose and glutamine derived carbons. We show here an unexpected role for PEPCK in promoting cancer cell proliferation in vitro and in vivo by increasing glucose and glutamine utilization toward anabolic metabolism. Unexpectedly, PEPCK also increased the synthesis of ribose from non-carbohydrate sources, such as glutamine, a phenomenon not previously described. Finally, we show that the effects of PEPCK on glucose metabolism and cell proliferation are in part mediated via activation of mTORC1. Taken together, these data demonstrate a role for PEPCK that links metabolic flux and anabolic pathways to cancer cell proliferation.

Mol Cancer Res. 2015 Oct;13(10):1408-20.   http://dx.doi.org:/10.1158/1541-7786.MCR-15-0048. Epub 2015 Jun 16.

Disruption of Proline Synthesis in Melanoma Inhibits Protein Production Mediated by the GCN2 Pathway.

Kardos GR¹, Wastyk HC², Robertson GP³. Author information

Many processes are deregulated in melanoma cells and one of those is protein production. Although much is known about protein synthesis in cancer cells, effective ways of therapeutically targeting this process remain an understudied area of research. A process that is upregulated in melanoma compared with normal melanocytes is proline biosynthesis, which has been linked to both oncogene and tumor suppressor pathways, suggesting an important convergent point for therapeutic intervention. Therefore, an RNAi screen of a kinase library was undertaken, identifying aldehyde dehydrogenase 18 family, member A1 (ALDH18A1) as a critically important gene in regulating melanoma cell growth through proline biosynthesis. Inhibition of ALDH18A1, the gene encoding pyrroline-5-carboxylate synthase (P5CS), significantly decreased cultured melanoma cell viability and tumor growth. Knockdown of P5CS using siRNA had no effect on apoptosis, autophagy, or the cell cycle but cell-doubling time increased dramatically suggesting that there was a general slowdown in cellular metabolism. Mechanistically, targeting ALDH18A1 activated the serine/threonine protein kinase GCN2 (general control nonderepressible 2) to inhibit protein synthesis, which could be reversed with proline supplementation. Thus, targeting ALDH18A1 in melanoma can be used to disrupt proline biosynthesis to limit cell metabolism thereby increasing the cellular doubling time mediated through the GCN2 pathway.  This study demonstrates that melanoma cells are sensitive to disruption of proline synthesis and provides a proof-of-concept that the proline synthesis pathway can be therapeutically targeted in melanoma tumors for tumor inhibitory efficacy. Mol Cancer Res; 13(10); 1408-20. ©2015 AACR.

J Natl Cancer Inst. 2015 Oct 12;108(1). pii: djv287.   http://dx.doi.org:/10.1093/jnci/djv287.

SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery.

Saxena N¹, Maio N¹, Crooks DR¹, Ricketts CJ¹, Yang Y¹, Wei MH¹, Fan TW¹, Lane AN¹, Sourbier C¹, Singh A¹, Killian JK¹, Meltzer PS¹, Vocke CD¹, Rouault TA¹, Linehan WM¹.  Author information

BACKGROUND:  Mutations in the Fe-S cluster-containing SDHB subunit of succinate dehydrogenase cause familial cancer syndromes. Recently the tripeptide motif L(I)YR was identified in the Fe-S recipient protein SDHB, to which the cochaperone HSC20 binds.

METHODS:   In order to characterize the metabolic basis of SDH-deficient cancers we performed stable isotope-resolved metabolomics in a novel SDHB-deficient renal cell carcinoma cell line and conducted bioinformatics and biochemical screening to analyze Fe-S cluster acquisition and assembly of SDH in the presence of other cancer-causing SDHB mutations.

RESULTS:

We found that the SDHB(R46Q) mutation in UOK269 cells disrupted binding of HSC20, causing rapid degradation of SDHB. In the absence of SDHB, respiration was undetectable in UOK269 cells, succinate was elevated to 351.4±63.2 nmol/mg cellular protein, and glutamine became the main source of TCA cycle metabolites through reductive carboxylation. Furthermore, HIF1α, but not HIF2α, increased markedly and the cells showed a strong DNA CpG island methylator phenotype (CIMP). Biochemical and bioinformatic screening revealed that 37% of disease-causing missense mutations in SDHB were located in either the L(I)YR Fe-S transfer motifs or in the 11 Fe-S cluster-ligating cysteines.

CONCLUSIONS:

These findings provide a conceptual framework for understanding how particular mutations disproportionately cause the loss of SDH activity, resulting in accumulation of succinate and metabolic remodeling in SDHB cancer syndromes.

 

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMPK-mTOR Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

1. L. Figarola, J. Singhal, J. D. Tompkins, G. W. Rogers, C. Warden, D. Horne, A. D. Riggs, S. Awasthi and S. S. Singhal.

J Biol Chem. 2015 Nov 3, [epub ahead of print]

 

CD47 Receptor Globally Regulates Metabolic Pathways That Control Resistance to Ionizing Radiation

1. W. Miller, D. R. Soto-Pantoja, A. L. Schwartz, J. M. Sipes, W. G. DeGraff, L. A. Ridnour, D. A. Wink and D. D. Roberts.

J Biol Chem. 2015 Oct 9, 290 (41): 24858-74.

 

Knockdown of PKM2 Suppresses Tumor Growth and Invasion in Lung Adenocarcinoma

1. Sun, A. Zhu, L. Zhang, J. Zhang, Z. Zhong and F. Wang.

Int J Mol Sci. 2015 Oct 15, 16 (10): 24574-87.

 

EglN2 associates with the NRF1-PGC1alpha complex and controls mitochondrial function in breast cancer

1. Zhang, C. Wang, X. Chen, M. Takada, C. Fan, X. Zheng, H. Wen, Y. Liu, C. Wang, R. G. Pestell, K. M. Aird, W. G. Kaelin, Jr., X. S. Liu and Q. Zhang.

EMBO J. 2015 Oct 22, [epub ahead of print]

 

Cancer Res. 2015 Oct 15;75(20):4429-36.    http://dx.doi.org:/10.1158/0008-5472.CAN-15-0074.

Mitochondrial Genetics Regulate Breast Cancer Tumorigenicity and Metastatic Potential.

Feeley KP¹, Bray AW¹, Westbrook DG¹, Johnson LW², Kesterson RA², Ballinger SW¹, Welch DR³.  Author information   

Current paradigms of carcinogenic risk suggest that genetic, hormonal, and environmental factors influence an individual’s predilection for developing metastatic breast cancer. Investigations of tumor latency and metastasis in mice have illustrated differences between inbred strains, but the possibility that mitochondrial genetic inheritance may contribute to such differences in vivo has not been directly tested. In this study, we tested this hypothesis in mitochondrial-nuclear exchange mice we generated, where cohorts shared identical nuclear backgrounds but different mtDNA genomes on the background of the PyMT transgenic mouse model of spontaneous mammary carcinoma. In this setting, we found that primary tumor latency and metastasis segregated with mtDNA, suggesting that mtDNA influences disease progression to a far greater extent than previously appreciated. Our findings prompt further investigation into metabolic differences controlled by mitochondrial process as a basis for understanding tumor development and metastasis in individual subjects. Importantly, differences in mitochondrial DNA are sufficient to fundamentally alter disease course in the PyMT mouse mammary tumor model, suggesting that functional metabolic differences direct early tumor growth and metastatic efficiency. Cancer Res; 75(20); 4429-36. ©2015 AACR.

 

Cancer Lett. 2015 Oct 29. pii: S0304-3835(15)00656-4.    http://dx.doi.org:/10.1016/j.canlet.2015.10.025. [Epub ahead of print]

Carboxyamidotriazole inhibits oxidative phosphorylation in cancer cells and exerts synergistic anti-cancer effect with glycolysis inhibition.

Ju R¹, Guo L¹, Li J¹, Zhu L¹, Yu X¹, Chen C¹, Chen W¹, Ye C², Zhang D³. Author information   

Targeting cancer cell metabolism is a promising strategy against cancer. Here, we confirmed that the anti-cancer drug carboxyamidotriazole (CAI) inhibited mitochondrial respiration in cancer cells for the first time and found a way to enhance its anti-cancer activity by further disturbing the energy metabolism. CAI promoted glucose uptake and lactate production when incubated with cancer cells. The oxidative phosphorylation (OXPHOS) in cancer cells was inhibited by CAI, and the decrease in the activity of the respiratory chain complex I could be one explanation. The anti-cancer effect of CAI was greatly potentiated when being combined with 2-deoxyglucose (2-DG). The cancer cells treated with the combination of CAI and 2-DG were arrested in G2/M phase. The apoptosis and necrosis rates were also increased. In a mouse xenograft model, this combination was well tolerated and retarded the tumor growth. The impairment of cancer cell survival was associated with significant cellular ATP decrease, suggesting that the combination of CAI and 2-DG could be one of the strategies to cause dual inhibition of energy pathways, which might be an effective therapeutic approach for a broad spectrum of tumors.

 

Cancer Immunol Res. 2015 Nov;3(11):1236-47.    http://dx.doi.org:/10.1158/2326-6066.CIR-15-0036. Epub 2015 May 29.
Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies.

Hossain F¹, Al-Khami AA², Wyczechowska D², Hernandez C², Zheng L², Reiss K³, Valle LD⁴, Trillo-Tinoco J², Maj T⁵, Zou W⁵, Rodriguez PC⁶, Ochoa AC⁷.  Author information

Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T-cell immunity and promoting malignant cell proliferation and migration. The therapeutic potential of blocking MDSC in tumors has been limited by their heterogeneity, plasticity, and resistance to various chemotherapy agents. Recent studies have highlighted the role of energy metabolic pathways in the differentiation and function of immune cells; however, the metabolic characteristics regulating MDSC remain unclear. We aimed to determine the energy metabolic pathway(s) used by MDSC, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhances antitumor therapies. Using several murine tumor models, we found that tumor-infiltrating MDSC (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied by an increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumption rate. Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSC and decreased their production of inhibitory cytokines. FAO inhibition alone significantly delayed tumor growth in a T-cell-dependent manner and enhanced the antitumor effect of adoptive T-cell therapy. Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSC immunosuppressive effects and induced a significant antitumor effect. Interestingly, a similar increase in fatty acid uptake and expression of FAO-related enzymes was found in human MDSC in peripheral blood and tumors. These results support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies. Cancer Immunol Res; 3(11); 1236-47. ©2015 AACR.

 

Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase

1. L. Judge, K. M. Owens, S. J. Pollock, C. F. Woeller, T. H. Thatcher, J. P. Williams, R. P. Phipps, P. J. Sime and R. M. Kottmann.

Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15, 309 (8): L879-87.

 

Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH

1. Yun, E. Mullarky, C. Lu, K. N. Bosch, A. Kavalier, K. Rivera, J. Roper, Chio, II, E. G. Giannopoulou, C. Rago, A. Muley, J. M. Asara, J. Paik, O. Elemento, Z. Chen, D. J. Pappin, L. E. Dow, N. Papadopoulos, S. S. Gross and L. C. Cantley.

Science. 2015 Nov 5, [epub ahead of print]

 

Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells

1. Zhang, J. Wang, H. Xing, Q. Li, Q. Zhao and J. Li.

Mol Cell Biochem. 2015 Nov 6, [epub ahead of print]

 

J Mol Cell Cardiol. 2015 Oct 23. pii: S0022-2828(15)30073-0.     http://dx.doi.org:/10.1016/j.yjmcc.2015.10.002. [Epub ahead of print]

GRK2 compromises cardiomyocyte mitochondrial function by diminishing fatty acid-mediated oxygen consumption and increasing superoxide levels.

Sato PY¹, Chuprun JK¹, Ibetti J¹, Cannavo A¹, Drosatos K¹, Elrod JW¹, Koch WJ².    Author information

The G protein-coupled receptor kinase-2 (GRK2) is upregulated in the injured heart and contributes to heart failure pathogenesis. GRK2 was recently shown to associate with mitochondria but its functional impact in myocytes due to this localization is unclear. This study was undertaken to determine the effect of elevated GRK2 on mitochondrial respiration in cardiomyocytes. Sub-fractionation of purified cardiac mitochondria revealed that basally GRK2 is found in multiple compartments. Overexpression of GRK2 in mouse cardiomyocytes resulted in an increased amount of mitochondrial-based superoxide. Inhibition of GRK2 increased oxygen consumption rates and ATP production. Moreover, fatty acid oxidation was found to be significantly impaired when GRK2 was elevated and was dependent on the catalytic activity and mitochondrial localization of this kinase. Our study shows that independent of cardiac injury, GRK2 is localized in the mitochondria and its kinase activity negatively impacts the function of this organelle by increasing superoxide levels and altering substrate utilization for energy production.

 

Br J Pharmacol. 2015 Oct 27. doi: 10.1111/bph.13377. [Epub ahead of print]

All-trans retinoic acid protects against doxorubicin-induced cardiotoxicity by activating the Erk2 signalling pathway.

Yang L¹, Luo C², Chen C¹, Wang X¹, Shi W¹, Liu J¹.   Author information     

BACKGROUND AND PURPOSE:

Doxorubicin (Dox) is a powerful antineoplastic agent for treating a wide range of cancers. However, doxorubicin cardiotoxicity of the heart has largely limited its clinical use. It is known that all-trans retinoic acid (ATRA) plays important roles in many cardiac biological processes, however, the protective effects of ATRA on doxorubicin cardiotoxicity remain unknown. Here, we studied the effect of ATRA on doxorubicin cardiotoxicity and underlying mechanisms.

EXPERIMENTAL APPROACHES:

Cellular viability assays, western blotting and mitochondrial respiration analyses were employed to evaluate the cellular response to ATRA in H9c2 cells and primary cardiomyocytes. Quantitative PCR (Polymerase Chain Reaction) and gene knockdown were performed to investigate the underlying molecular mechanisms of ATRA’s effects on doxorubicin cardiotoxicity.

KEY RESULTS:

ATRA significantly inhibited doxorubicin-induced apoptosis in H9c2 cells and primary cardiomyocytes. ATRA was more effective against doxorubicin cardiotoxicity than resveratrol and dexrazoxane. ATRA also suppressed reactive oxygen species (ROS) generation, and restored the expression level of mRNA and proteins in phase II detoxifying enzyme system: Nrf2 (nuclear factor-E2-related factor 2), MnSOD (manganese superoxide dismutase), HO-1 (heme oxygenase1) as well as mitochondrial function (mitochondrial membrane integrity, mitochondrial DNA copy numbers, mitochondrial respiration capacity, biogenesis and dynamics). Both Erk1/2 (extracellular signal-regulated kinase1/2) inhibitor (U0126) and Erk2 siRNA, but not Erk1 siRNA, abolished the protective effect of ATRA against doxorubicin-induced toxicity in H9c2 cells. Remarkably, ATRA did not compromise the anticancer efficacy of doxorubicin in gastric carcinoma cells.

CONCLUSION AND IMPLICATION:

ATRA protected cardiomyocytes against doxorubicin-induced toxicity by activating the Erk2 pathway without compromising the anticancer efficacy of doxorubicin. Therefore, ATRA may be a promising candidate as a cardioprotective agent against doxorubicin cardiotoxicity.

 

Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation

1. Colak, O. Pougovkina, L. Dai, M. Tan, H. Te Brinke, H. Huang, Z. Cheng, J. Park, X. Wan, X. Liu, W. W. Yue, R. J. Wanders, J. W. Locasale, D. B. Lombard, V. C. de Boer and Y. Zhao.

Mol Cell Proteomics. 2015 Nov 1, 14 (11): 3056-71.

 

Foxg1 localizes to mitochondria and coordinates cell differentiation and bioenergetics

1. Pancrazi, G. Di Benedetto, L. Colombaioni, G. Della Sala, G. Testa, F. Olimpico, A. Reyes, M. Zeviani, T. Pozzan and M. Costa.

Proc Natl Acad Sci U S A. 2015 Oct 27, 112(45): 13910-5.

 

Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia

1. E. Hjelm, B. Rollins, F. Mamdani, J. C. Lauterborn, G. Kirov, G. Lynch, C. M. Gall, A. Sequeira and M. P. Vawter.

Mol Neuropsychiatry. 2015 Nov 1, 1 (4): 201-219.

 

Metabolic Reprogramming Is Required for Myofibroblast Contractility and Differentiation

1. Bernard, N. J. Logsdon, S. Ravi, N. Xie, B. P. Persons, S. Rangarajan, J. W. Zmijewski, K. Mitra, G. Liu, V. M. Darley-Usmar and V. J. Thannickal.

J Biol Chem. 2015 Oct 16, 290 (42): 25427-38.

 

J Biol Chem. 2015 Oct 23;290(43):25834-46.    http://dx.doi.org:/10.1074/jbc.M115.658815. Epub 2015 Sep 4.

Kinome Screen Identifies PFKFB3 and Glucose Metabolism as Important Regulators of the Insulin/Insulin-like Growth Factor (IGF)-1 Signaling Pathway.

Trefely S¹, Khoo PS², Krycer JR³, Chaudhuri R³, Fazakerley DJ³, Parker BL³, Sultani G¹, Lee J⁴, Stephan JP⁴, Torres E⁴, Jung K⁴, Kuijl C⁴, James DE⁵,Junutula JR⁶, Stöckli J⁷.   Author information

The insulin/insulin-like growth factor (IGF)-1 signaling pathway (ISP) plays a fundamental role in long term health in a range of organisms. Protein kinases including Akt and ERK are intimately involved in the ISP. To identify other kinases that may participate in this pathway or intersect with it in a regulatory manner, we performed a whole kinome (779 kinases) siRNA screen for positive or negative regulators of the ISP, using GLUT4 translocation to the cell surface as an output for pathway activity. We identified PFKFB3, a positive regulator of glycolysis that is highly expressed in cancer cells and adipocytes, as a positive ISP regulator. Pharmacological inhibition of PFKFB3 suppressed insulin-stimulated glucose uptake, GLUT4 translocation, and Akt signaling in 3T3-L1 adipocytes. In contrast, overexpression of PFKFB3 in HEK293 cells potentiated insulin-dependent phosphorylation of Akt and Akt substrates. Furthermore, pharmacological modulation of glycolysis in 3T3-L1 adipocytes affected Akt phosphorylation. These data add to an emerging body of evidence that metabolism plays a central role in regulating numerous biological processes including the ISP. Our findings have important implications for diseases such as type 2 diabetes and cancer that are characterized by marked disruption of both metabolism and growth factor signaling.

 

FASEB J. 2015 Oct 19.    http://dx.doi.org:/pii: fj.15-276360. [Epub ahead of print]

Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle.

Cho Y¹, Hazen BC¹, Gandra PG¹, Ward SR¹, Schenk S¹, Russell AP¹, Kralli A².  Author information

Skeletal muscle mitochondrial content and oxidative capacity are important determinants of muscle function and whole-body health. Mitochondrial content and function are enhanced by endurance exercise and impaired in states or diseases where muscle function is compromised, such as myopathies, muscular dystrophies, neuromuscular diseases, and age-related muscle atrophy. Hence, elucidating the mechanisms that control muscle mitochondrial content and oxidative function can provide new insights into states and diseases that affect muscle health. In past studies, we identified Perm1 (PPARGC1- and ESRR-induced regulator, muscle 1) as a gene induced by endurance exercise in skeletal muscle, and regulating mitochondrial oxidative function in cultured myotubes. The capacity of Perm1 to regulate muscle mitochondrial content and function in vivo is not yet known. In this study, we use adeno-associated viral (AAV) vectors to increase Perm1 expression in skeletal muscles of 4-wk-old mice. Compared to control vector, AAV1-Perm1 leads to significant increases in mitochondrial content and oxidative capacity (by 40-80%). Moreover, AAV1-Perm1-transduced muscles show increased capillary density and resistance to fatigue (by 33 and 31%, respectively), without prominent changes in fiber-type composition. These findings suggest that Perm1 selectively regulates mitochondrial biogenesis and oxidative function, and implicate Perm1 in muscle adaptations that also occur in response to endurance exercise.-Cho, Y., Hazen, B. C., Gandra, P. G., Ward, S. R., Schenk, S., Russell, A. P., Kralli, A. Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle.

 

Cell Death Dis. 2015 Oct 29;6:e1944.    http://dx.doi.org:/10.1038/cddis.2015.306.

A conserved MADS-box phosphorylation motif regulates differentiation and mitochondrial function in skeletal, cardiac, and smooth muscle cells.

Mughal W^1,2, Nguyen L², Pustylnik S³, da Silva Rosa SC^1,2, Piotrowski S^1,2, Chapman D^2,4, Du M³, Alli NS³, Grigull J^3,5, Halayko AJ^6,7, Aliani M⁸, Topham MK⁹, Epand RM¹⁰, Hatch GM^2,11, Pereira TJ^2,11, Kereliuk S^2,11, McDermott JC³, Rampitsch C¹², Dolinsky VW^2,11, Gordon JW^1,2,4.   Author information

Exposure to metabolic disease during fetal development alters cellular differentiation and perturbs metabolic homeostasis, but the underlying molecular regulators of this phenomenon in muscle cells are not completely understood. To address this, we undertook a computational approach to identify cooperating partners of the myocyte enhancer factor-2 (MEF2) family of transcription factors, known regulators of muscle differentiation and metabolic function. We demonstrate that MEF2 and the serum response factor (SRF) collaboratively regulate the expression of numerous muscle-specific genes, including microRNA-133a (miR-133a). Using tandem mass spectrometry techniques, we identify a conserved phosphorylation motif within the MEF2 and SRF Mcm1 Agamous Deficiens SRF (MADS)-box that regulates miR-133a expression and mitochondrial function in response to a lipotoxic signal. Furthermore, reconstitution of MEF2 function by expression of a neutralizing mutation in this identified phosphorylation motif restores miR-133a expression and mitochondrial membrane potential during lipotoxicity. Mechanistically, we demonstrate that miR-133a regulates mitochondrial function through translational inhibition of a mitophagy and cell death modulating protein, called Nix. Finally, we show that rodents exposed to gestational diabetes during fetal development display muscle diacylglycerol accumulation, concurrent with insulin resistance, reduced miR-133a, and elevated Nix expression, as young adult rats. Given the diverse roles of miR-133a and Nix in regulating mitochondrial function, and proliferation in certain cancers, dysregulation of this genetic pathway may have broad implications involving insulin resistance, cardiovascular disease, and cancer biology.

 

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Developmental biology

Posted in Personalized and Precision Medicine & Genomic Research, Regenerative Biology and Medicine, Signaling, Signaling & Cell Circuits, Stem Cells for Regenerative Medicine, Tissue Engineering and Regenerative Medicine, Translational Research, Translational Science, tagged cloning and sequencing the first keratins, skin cancer, Stem Cell Biology and Regenerative Medicine on September 8, 2015| Leave a Comment »

Developmental biology

Larry H. Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Intelligence

Series E. 2, 7.4

Lucy Shapiro (born July 16, 1940, New York City) is an American developmental biologist. She is a professor of Developmental Biology at the Stanford University School of Medicine. She is the Ludwig Professor of Cancer Research and the director of the Beckman Center for Molecular and Genetic Medicine.^[1] She founded a new field in developmental biology, using microorganisms to examine fundamental questions in developmental biology. Her work has furthered understanding of the basis of stem cell function and the generation of biological diversity.^[2] Her ideas have revolutionized understanding of bacterial genetic networks and helped researchers to develop novel drugs to fight antibiotic resistance and emerging infectious diseases.^[3] In 2013, Dr. Shapiro was presented with the 2011 National Medal of Science, which is given to individuals who have demonstrated “an outstanding breadth of knowledge in their field.”^[3][4]

 

Lucy

Shapiro, PhD

Stanford University

Virginia and D.K. Ludwig Professor
Professor, Developmental Biology
Director of the Beckman Center for Molecular and Genetic Medicine
Stanford University, Palo Alto, California, USA

The Ludwig Institute for Cancer Research Ltd is an international not-for-profit organization with a 40-year legacy of pioneering cancer discoveries. The Institute provides its scientists from around the world with the resources and the flexibility to realize the life-changing potential of their work and see their discoveries advance human health. This philosophy, combined with robust translational programs, maximizes the potential of breakthrough discoveries to be more attractive for commercial development.

The Ludwig Institute conducts its own research and clinical trials, making it a bridge from the most basic questions of life to the most pressing needs of cancer care. Since its inception, the Institute has invested more than $1.7 billion of its own resources in cancer research, and has an endowment valued at $1.2 billion. The Institute’s assets are managed by the LICR Fund.

Dr. Lucy Shapiro, DF, Ph.D serves as Virginia and D.K. Ludwig Professor of Cancer Research in the Department of Developmental Biology and Director of the Beckman Center for Molecular and Genetic Medicine at the Stanford University School of Medicine where she has been a faculty member since 1989. Dr. Shapiro founded Stanford University’s Department of Developmental Biology in 1989 and served as its Chairperson from 1989 to 1997.

Lucy Shapiro Ph.D.

Co-Founder, Co-Chair of Scientific Advisory Board, Director and Member of Nominating & Corporate Governance Committee,Anacor Pharmaceuticals, Inc.

 

Age	Total Calculated Compensation	This person is connected to 46 board members in 3 different organizations across 6 different industries. See Board Relationships
74	$222,846

Lucy Shapiro named 2015 commencement speaker

Using her unique worldview as both artist and scientist, Shapiro revolutionized the field of developmental biology and set the stage for the new field of systems biology.

Lucy Shapiro

Stanford developmental biologist Lucy Shapiro, PhD, whose unique worldview has revolutionized the understanding of the bacterial cell as an engineering paradigm, will be the commencement speaker for the School of Medicine Class of 2015.

The diploma ceremony will be held June 13 from 11 a.m. to 1 p.m. on Alumni Green, followed by a luncheon at 1 p.m. on the Dean’s Lawn.

Shapiro, the Virginia and D. K. Ludwig Professor, has spent her career on the leading edge of developmental biology. She is the recipient of numerous awards, including the National Medal of Science in 2012 and the 2014 Pearl Meister Greengard Prize, which celebrates the achievements of outstanding women in science.

Shapiro, director of the Beckman Center for Molecular and Genetic Medicine, has been a faculty member since 1989, when she founded the medical school’s Department of Developmental Biology.

A painter who studied both biology and the fine arts as an undergraduate, Shapiro said that she sees science as part of the world of art. She began her career as a scientist focused on finding new ways of looking at and understanding living things, much as an artist does. She started by hunting for the simplest organism she could find — a bacterial cell — and then studying its molecular mechanisms. Her research into the genetic circuitry of these cells paved the way for new antibiotics. Her use of the microorganism as a model also set the stage for the emerging field of systems biology.

She has served in advisory roles in both the Clinton and George W. Bush administrations on the threat of infectious disease in developing countries. She has said that increasing levels of both antibiotic resistance and novel infectious agents are likely to be a larger threat to the world than bioterrorism. Shapiro also started a biotech company to test and develop antibiotic and antifungal medications.

Use science to make world a better place, graduates told

At the medical school’s commencement, Lucy Shapiro described how years of solitary work in the laboratory led her to influence public policy and battle the growing threat of infectious disease on the global stage.

JUN 152015

Commencement speaker Lucy Shapiro discussed how she raised alarms about the threat of emerging infectious diseases, drug-resistant pathogens “and a poor to nonexistent drug pipeline.”
Norbert von der Groeben

Developmental biologist Lucy Shapiro, PhD, told the 2015 School of Medicine graduates how, as a basic scientist who spent most of her life studying single-celled bacteria, she stepped out of her laboratory and onto the global stage to try to help the world avert a potential disaster.

“About 15 years ago, I sat up and looked around me and found that we were in the midst of a perfect storm,” said Shapiro, the Virginia and D. K. Ludwig Professor, speaking at the school’s commencement June 13 on Alumni Green. “There was a global tide of emerging infectious diseases, rampant antibiotic and antiviral resistance amongst all pathogens and a poor to nonexistent drug pipeline.

“For me the alarm bells went off, and I was convinced that I had to try and do something. Let me tell you the story of how I stepped out of my comfort zone. I launched a one-woman attack.”

She took any speaking engagement she could get to educate the public about antibiotic resistance; walked the corridors of power in Washington, D.C., lobbying politicians about the dangers of emerging infectious diseases; and used discoveries from her lab on the single-celled Caulobacter bacterium to develop new, effective disease-fighting drugs.

Bench-to-bedside for a better world

A recipient of the National Medal of Science, Shapiro exhorted the graduates to be unafraid of breaking out of their comfort zones and to use science to improve the human condition. Bridging the gap between the lab and the clinic can make the world a better place, she said.

Lloyd Minor, MD, dean of the School of Medicine, also emphasized the importance of bench-to-bedside work in his remarks to the graduates. There has never been a better time for shepherding advances in basic research into the clinic, he said.

Kristy Red-Horse, assistant professor of biology, hoods Katharina Sophia Volz, the first-ever graduate of the Interdepartmental Program in Stem Cell Biology and Regenerative Medicine.
Norbert von der Groeben

“You are beginning your careers at an unprecedented time of opportunities for biomedical science and for human health,” he said.

This year’s class of 195 graduates comprised 78 students who earned PhDs, 78 who earned medical degrees and 39 who earned master’s degrees. It included Katharina Sophia Volz, the first-ever graduate of the Interdepartmental Program in Stem Cell Biology and Regenerative Medicine — the first doctoral program in the nation focusing on stem cell science and translating it to patient care.

Volz, whose work in the lab has opened the doors to improvements in clinical care for heart patients, said Stanford Medicine is the place to be for scientists who want to make a difference in the world.

“Everybody here is reaching for the stars. We can do the best work here of anywhere,” said Volz, 28, a native of Ulm, Germany, the birthplace of Albert Einstein. She has worked in 10 different labs across the globe. Her father and mother, Johannes and Luise Volz, traveled from Germany to celebrate with her.

“I’ve never been in a more supportive environment,” said Volz, who discovered the progenitors to the muscle layer around the coronary arteries, a finding with implications for regenerative medicine and finding treatments for coronary artery disease.

Well-wishers, garlands and fussy babies

Some in the crowd of well-wishers, seated under a giant white tent, held garlands of flowers for the graduates, while toddlers ran around the lawn and babies fussed and cried. The two student speakers added humor and pathos to the occasion, with memories of their years of hard work and discovery.

“I’d like to run one last experiment,” said Francisco Jose Emilio Gimenez, a PhD graduate in biomedical information. “Who here had serious doubts they would ever finish their PhD?”

Brook Barajas, who earned a PhD in cancer biology, holds her 15-month-old son Sebastian.
Norbert von der Groeben

The dozens of hands shooting up from the stage were followed by laughter from the crowd.

Meghan Galligan, a medical degree graduate, said she was both nervous to be in front of the crowd and concerned about whether her puffy black graduation cap would stay put. “I’m wearing a French pastry hat and worried it’s going to fall off,” she said.

Her years of education to become a physician changed the day she entered clinical care training. “From the day we started clinics, we would really never be the same as those bright-eyed individuals who gathered here for orientation,” she said. “How could we be after gaining such privileged access into the human condition?”

Role as government adviser

Shapiro’s desire to improve the human condition led her out of the lab to the nation’s capital. She has since served in advisory roles in the administrations of Bill Clinton and George W. Bush on the threat of infectious disease in developing countries. Now director of the Beckman Center for Molecular and Genetic Medicine at Stanford, Shapiro has been a faculty member since 1989. She was founding chair of the Department of Developmental Biology and also started a biotech company in Palo Alto to test and develop antibiotics and antifungals.

Her lab at Stanford made breakthroughs in understanding the genetic circuitry of simple cells, setting the stage for the development of new antibiotics. Shapiro told the audience that over the 25 years that she has worked at the School of Medicine, she has seen a major shift in the connection between those who conduct research in labs and those who care for patients in clinics.

“We have finally learned to talk to each other,” Shapiro said. “I’ve watched the convergence of basic research and clinical applications without the loss of curiosity-driven research in the lab or patient-focused care in the clinic.”

Monica Eneriz-Wiemer, who earned a medical degree, hugs her mother Gloria Eneriz on June 13 before the School of Medicine’s diploma ceremony.
Norbert von der Groeben

This new connection, she said, is key to the future of global health.

“This is no ordinary time, from shattering political unrest in the Middle East and North Africa and the consequent flood of immigrant populations that serves as a petri dish for infectious pathogens, to global shifts in urban environments, to climate change, which is having substantial impact on health … all contributing to the appearance of old pathogens in new places and new pathogens for which we have no immunity.

“We here must care about an Ebola outbreak 8,000 miles away in West Africa; we here must care about a cholera outbreak in Haiti; we wait for the consequences of the earthquake in Nepal. We live in a global village.”

This is your time to shape the future, Shapiro told the graduates.

“Step out of your comfort zone and follow your intuition,” she said. “Don’t be afraid of taking chances. Ask, ‘How can I change what’s wrong?’ ”

In closing remarks, Laurie Weisberg, MD, president of the Stanford Medicine Alumni Association and clinical professor of medicine at UC San Francisco, also encouraged students to step outside of their comfort zone.

“You may be the most brilliant, creative and productive scientist, clinician, writer or entrepreneur, but you’ll never know if you don’t embrace uncertainty, take on a new challenge, and give it a try,” she said.  “To do what you love, and do it well, with all your heart — that’s what most important.

• 

  ByTRACIE WHITE

  Tracie White is a science writer for the medical school’s Office of Communication & Public Affairs. Email her attracie.white@stanford.edu.

---

Stanford Medicine integrates research, medical education and health care at its three institutions – Stanford University School of Medicine, Stanford Health Care (formerly Stanford Hospital & Clinics), and Lucile Packard Children’s Hospital Stanford.

Lucy Shapiro – 2011 National Medal of Science – YouTube

http://www.youtube.com/watch%3Fv%3D9xiPLvJnmhU  Feb 8, 2013

… Lucy Shapiro, Stanford University – National Medal of Science 2011 for the pioneering discovery that the bacterial cell is controlled by an …

 

Elaine Fuchs, Ph.D.
Investigator, Howard Hughes Medical Institute
Rebecca C. Lancefield Professor
Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development

Skin harbors our largest reservoirs of stem cells. To maintain the body barrier, epidermis constantly self-renews and hair follicles undergo cyclical bouts of activity. Both stem cell compartments participate in repairing tissue damage after injury. Dr. Fuchs studies where adult stem cells come from, how they make tissues, how they repair wounds and how stem cells malfunction in cancers. Her group focuses on the mechanisms that impart skin stem cells with the ability to self-renew, develop and maintain tissues, and how these cells respond to external cues, and depart from their niche to accomplish these tasks.

Nature Reviews Genetics 13, 381 (June 2012) |   http://dx.doi.org:/10.1038/nrg3252

The 2012 March of Dimes Prize in Developmental Biology has been jointly awarded to Elaine Fuchs, of the Rockefeller University and Howard Hughes Medical Institute, and to Howard Green, of Harvard Medical School, for their pioneering research on the molecular workings of skin stem cells and inherited skin disorders. The prize recognizes researchers whose work has contributed to our understanding of the science that underlies birth defects.

Elaine Fuchs

Fiona Watt

http://jcs.biologists.org/content/117/21/4877.full

• WOMEN IN CELL SCIENCE

http://dx.doi.org:/10.1242/​jcs.01408  Oct 1, 2004 J Cell Sci 117, 4877-4879.

Elaine Fuchs was born in the United States and raised just outside Chicago. In 1972 she graduated with a B.S. and highest distinction in the Chemical Sciences from the University of Illinois. Her undergraduate thesis research in physical chemistry focused on the electrodiffusion of nickel through quartz. She moved from Illinois to Princeton University to study for her PhD in Biochemistry, investigating changes in bacterial cell walls during sporulation in Bacillus megaterium. In 1977, she joined Howard Green, then at Massachusetts Institute of Technology (MIT), for her postdoctoral studies. There, she focused on elucidating the mechanisms underlying the balance between growth and differentiation in epidermal keratinocytes, a system and research area that continues to fascinate her today. In 1980, she was recruited to the University of Chicago, where she moved up through the ranks to the position of Amgen Professor of Molecular Genetics and Cell Biology and Investigator of the Howard Hughes Medical Institute. She moved to The Rockefeller University in 2002, where she is now the Rebecca C. Lancefield Professor of Mammalian Cell Biology and Development.

Elaine’s research has encompassed identifying and characterizing the keratin genes expressed in human skin, understanding the transcriptional mechanisms underlying gene expression and differentiation in the epidermis and hair follicles, and revealing roles for Wnt and BMP signaling in skin. Currently, her lab’s focus is on understanding the niche for multipotent stem cells in skin. The thread that ties her research areas together is epithelial morphogenesis, understanding how external cues transmit their signals to elicit changes in transcription, cytoskeletal architecture and adhesion to establish the epidermis and hair follicles.

In the interview that follows, Fiona Watt, Editor-in-Chief of JCS, asks Elaine about her experiences as a woman in science.

FMW:How has your research career impacted on your personal life and vice versa?

EF: My father was a geochemist who specialized in meteorites at Argonne National Laboratories. My aunt, who lived in the house next door, was a biologist at Argonne, and an ardent feminist. My sister, four years my senior, is now a neuroscientist. My mother is a housewife, who loves gardening and cooking and used to play piano and paint in oils. Growing up in such a family, and with farm fields, creeks and ponds in the near vicinity, I developed a deep interest in science that has carried me through my professional life.

If I think back to the family influences that shaped my choice of career, I remember that my Dad strongly advocated my being an elementary school teacher. My aunt, his sister, was denied admission to medical school and she encouraged me to go into medicine. My mom told me that she thought I was a good cook and therefore I should become a chemist. My older sis was my idol, although I found her intelligence intimidating. She thought I should become an anthropologist. So, in contrast to my close friend and former colleague Susan Lindquist (now director of the Whitehead Institute at MIT), I was strongly encouraged by my family to go to college and do something with my life. I chose the University of Illinois at Urbana (my Dad told me that if there was a good reason why he should spend more than $2000 a year on my education, we should sit down and discuss the matter – otherwise, I should select either University of Illinois, our State school, or University of Chicago, where he got a tuition break. I vowed NOT to go to University of Chicago, because my sis, Dad and aunt went there, and I wanted to be different).

At the University of Illinois, I was one of three women in an undergraduate physics class of 200. My perception (shaped at least in part by the general aura of the scientific community at the time) was that, if I was to be accepted as a smart student, I probably needed to perform near or at the top of my class. I subsequently began studying very long hours, forgoing sleep and even studying while eating meals in the student cafeteria and while picketing classes during Vietnam War protests. Although my near perfect performances on tough physics and chemistry exams may have turned a few heads, I don’t feel that it served the deeper purpose of education, nor did it instill in me a long-standing love for these fields.⇓

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Elaine Fuchs in her lab in 1980.

By contrast, my participation in Vietnam War protests had a deeper impact on me, and I decided to apply to the Peace Corps. Having spent my electives taking Spanish and Latin American history, I was hoping to get accepted to go to Chile, which was headed by Allende, a liberal democratic Marxist. I was instead accepted to Uganda, which was headed by Idi Amin, a ruthless tyrant. It was then that I began in earnest contemplating graduate school, choosing Princeton’s Biochemistry Department, to move from physical sciences into the realm of more medically oriented science. I always suspected that my father was somehow behind the decision by the Peace Corps to send me to Uganda, but in the end going to graduate school was probably the right choice for me.

Not having taken biology since high school, I gravitated towards the most chemically oriented labs at Princeton. When I went to visit Bruce Alberts, he informed me that he only took the best students, which I was certain did not mean me. Marc Kirschner was no longer focused on physical biochemistry, but instead had begun working with disgusting-looking frogs. I settled on a Professor who had been quite open about his views that women should not be in science. Despite the fact that I was viewed by my mentor as a major disappointment relative to a fellow male graduate student who joined the same lab, I did learn from my mentor how to do well-controlled experiments, for which I’ve been forever grateful. Twenty years later, my mentor’s views regarding my relative lack of scientific skills even seemed to soften a bit.

Although I received my PhD in biochemistry, my education had not been very typical. I graduated without yet isolating protein, RNA or DNA. However, I had been frugal with my $3000/year graduate stipend, and had managed to travel (3rd class) through India, Nepal, Guatemala, Mexico, Peru, Bolivia, Ecuador, Turkey, Greece and Egypt (I’ve still never gotten to Chile or Uganda). In retrospect, I understand why my advisor had not taken me seriously!

Somehow, I managed to be accepted into the lab of Howard Green at MIT, and during my postdoctoral years, I limited my travel to Morocco, and began in earnest doing experiments. I chose Howard’s lab, because he was one of the pioneers in mammalian stem cell biology. He had developed methods to culture human epidermal stem cells under conditions where they could be maintained and propagated. I was yearning to switch model systems from bacteria to humans, hoping that my research might be more medically applicable, and I wanted to study the biochemical mechanisms underlying the balance between growth and differentiation in normal human cells. The system seemed ideal, and led me to become a skin biologist. Mouse genetics came later in my career after I was appointed to the HHMI at the University of Chicago, and had the resources to complement the culture system.

My experience at MIT had a powerful impact on my career. Howard Green was a quintessential cell biologist, which was something completely new to me. Nearly every lab at MIT was humming with brilliant postdocs, and I rapidly got hooked on the excitement of the science around me. I began to think that perhaps a scientific career might even be a possible goal for me – at least at some small teaching college or state university. After my first year at MIT, my advisor from Princeton nominated me for an Assistant Professorship at the University of Chicago, something that I assumed was to be a trial run for an academic job later down the road. I viewed the invitation to speak as a free trip home to visit my family, and was quite amazed when I subsequently received a job offer. It was only then when I began to realize that somebody must think more highly of my accomplishments than I did. My family’s pressure to accept the position was relentless and so I began an academic career as an independent scientist, feeling at the base of a totem pole of fantastic colleagues.

FMW:What changes for women in science have you observed during the course of your career?

EF: At Chicago, I was the first woman in a department of 15 biochemistry faculty members. But Janet Rowley, who already was a member of the National Academy of Sciences and a famous cytogeneticist, was in the Department of Medicine, and she sent hand-written notes congratulating me on every small success that would come my way. This inspired me, as did meeting Susan Lindquist in the Department of Biology, who became my long-standing close friend and colleague. In 1982, Sue also introduced me to David Hansen, to whom I have been happily married for 16 years!

Chicago reorganized their biological sciences departments in 1985, and Sue, Janet, several other women and I all chose to join the same Department, Molecular Genetics and Cell Biology. All of a sudden, women faculty members were in abundance and a force to be reckoned with. This and fantastic students became an endless source of enjoyment for me, and I remained at Chicago for over 20 years.

I feel that although there is still considerable work to be done to pave the way for women in science, the situation has improved considerably during the course of my career. Women are now routinely asked and elected to serve the scientific community in important ways. In this regard, I have served on the Advisory Council for the Director of the NIH, the Council of the National Academy of Sciences (NAS) and was President of the American Society of Cell Biology. In addition, major scientific organizations have cracked the door open wider for women, and I certainly feel fortunate to have been elected by my colleagues to the NAS, the Institute of Medicine and the American Academy of Arts and Sciences. I also feel honored to have received recognition from my colleagues through a number of scientific achievement awards, including the Richard Lounsbery Award from the NAS and an honorary doctorate degree from Mt Sinai and New York University Medical School. As women continue to make their way in the scientific community at all levels and in greater numbers, we will continue to see a rise in the creativity, reflection and breadth of thinking that is so necessary to move science forward.

FMW:Do you feel that being a woman is an inherent advantage/disadvantage for a career in science? Why?

EF: I can’t say that it is or isn’t, but for me the discrimination I have faced personally has served as an inspiration and a challenge to do better, not as an impediment to my career. The one thing I do feel now is that it is important for senior women to remember that the road for women scientists is not always an easy one. There is still substantial room for the scientific community to grow in the realization that, by opening the door to women, it is going to raise the level of scientific excellence. Senior women who are recognized by their peers as being successful have a responsibility to help educate those scientists who haven’t quite accepted this important message. And we have a responsibility to maintain the highest scientific and ethical standards and to serve as the best role models we can for the younger generation of outstanding scientists – both men and women – who are rising through the ranks. Leading by good example is still the best way to diffuse the now more subtle and less vocal, but nevertheless lingering, discrimination and dogmatism against women scientists within our scientific community.

No discussion of women and careers is complete without addressing the issue of children and motherhood. In my case, I’m afraid I don’t serve as a good role model because I don’t have children. However, I’d like to emphasize that this was a decision that my husband and I consciously made together. I’m married to the Director of Philosophy and Education at Teachers’ College, Columbia University, and for the past 20 years that we’ve known one another, we’ve enjoyed traveling the world, going to operas, symphony and chamber music concerts, eating leisurely dinners, dancing, swimming, quiet reflection, education and service to the broader community. We love our nieces and nephews, but children were not a high priority for our lives together. In another world, things might be different. However, I certainly don’t view this decision as a sacrifice that I had to make for my science.

FMW:What are your remaining career ambitions?

EF: I made the decision to move to Rockefeller in 2002 because it provided an exceptional constellation of world-renowned colleagues, generating a rich and stimulating new environment for the 17 postdocs and technicians who moved with me. Our research has progressively moved to the field of morphogenesis – understanding the molecular process that begins with a single stem cell and ends with a functional tissue, either epidermis or hair follicles. Characteristic of my checkered past, the research is a blend of biochemistry, molecular biology, cell and developmental biology, and the area enables us to combine our interests in signal transduction, transcriptional regulation, cytoskeletal dynamics and cell adhesion. The caliber of my students and postdocs keeps escalating, and the science continues to keep me in the lab nights and weekends, as it did when I was a postdoctoral fellow. Each day brings new challenges, and there is certainly no doubt now that the flame of excitement and interest in scientific discovery and education burns eternally within me. There is no `last’ objective – only new horizons and challenges. The revolution in biology that I have experienced in my own career tells me not to predict what my next objective will be.

I feel strongly that we make of our lives what we put into them. To succeed in a scientific career in academia takes motivation, commitment, effort, thought, creativity, intelligence, teaching skills, technical talent, organization, leadership, oral and writing skills, compassion and a strong sense of ethics. I know I’ve left out many other essential traits. Very few scientists have all these attributes, but we can each achieve a high degree of satisfaction if not success through honing the subset of attributes that we do have. I know that for me, the more I work on becoming a better scientist, mentor and participator in our scientific community, the richer all aspects of my life become.

• © The Company of Biologists Limited 2004

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Elaine Fuchs: A love for science that’s more than skin deep

• Text and Interview by Ben Short

  bshort@rockefeller.edu

JCB Dec 28, 2009;  187(7): 938-939  http://dx.doi.org:/10.1083/jcb.1877pi

Elaine Fuchs has collected many awards in her 30 years researching mammalian skin development, but it’s hard to beat the two prizes she received in late 2009. Shortly before winning the prestigious L’Oreál-UNESCO award for women in science, Fuchs was awarded the National Medal of Science—the US’s highest honor for outstanding scientific contributions.

After studying bacterial sporulation as a PhD student with Charles Gilvarg at Princeton, Fuchs joined Howard Green’s laboratory at MIT, where she investigated the expression of keratins in differentiating skin cells (1, 2). Fuchs then returned to her native Illinois to begin her own laboratory at the University of Chicago, and stayed for more than 20 years before moving to The Rockefeller University in New York in 2002. Fuchs’ research has touched on many aspects of skin differentiation and function. Asked to pick her favorite work, she chooses her pioneering use of mouse genetics to identify mutant keratins as the cause of several human skin diseases (3, 4). She also mentions the generation of super furry mice by expressing a stabilized version of the transcription factor β-catenin (5) as well as the identification and characterization of a multipotent stem cell population in the hair follicle (6, 7). In a recent interview, Fuchs discussed her latest awards, and explained why the skin continues to hold her interest.

Elaine Fuchs

Is it true that you refused to take the exam for graduate school entry?   

Yes! [laughs] I was graduating near the top of my class from a very good university and I felt that the Graduate Record Examination wasn’t testing my real knowledge, but rather how I could perform in a written exam. So I decided that perhaps they’d appreciate some creative writing instead. I wrote three pages explaining the reasons why I was not going to be taking my GRE, and I sent it along with my applications.

I got accepted everywhere, but it’s quite unlikely that I would be admitted to any graduate program in the US today. I don’t think professors are as open-minded toward rebellious students as they were during the Vietnam War era.

How did you decide to go to Howard Green’s laboratory for your postdoc?

I had been working on bacterial sporulation and, in the course of that, I studied bacterial cell walls. Many antibiotics target the enzymes that synthesize cell walls, and that medical aspect was what I really liked about my science.

To maintain my interest in biomedical research, I decided to switch to the growth and differentiation of human cells, but I knew I was going to need a good culture system. Howard was a cell culture guru—he developed the use of human epidermal cells as well as the 3T3L1 line for adipocyte differentiation. Almost everyone else was using transformed mammalian cells at the time and I thought these were great systems to study—I still do.

And you’ve worked on skin ever since—what has captivated you for so long?

Skin is such a complex organ. We focus on the epithelium, but epithelial–mesenchymal interactions are very important in dictating whether keratinocyte stem cells will stratify to make an epidermis or differentiate into a sebaceous gland or hair follicle. How does that happen? How do you start with a stem cell and build a tissue? There are lots of facets to the problem, ranging from transcription to cell–cell and cell–substratum interactions. There’s this endless array of signals from the environment that, in a sense, encompasses almost every aspect of biology.

So even though we still work on skin as a model system, we continue to ask different questions. We spent 10 years working on keratins, but if I’d stuck with that, I might have burned myself out. I learned early on in my career that it’s important to choose a problem you’re interested in, even if you don’t yet know the technology you need to address it. I think people get into ruts when they become very good at something and do it over and over again. What we’re doing now is very different to what we were doing several years ago, and we continue to try novel and original approaches.

One of those original approaches was using transgenic mice to link keratins with human genetic diseases…

After cloning and sequencing the first keratins, we’d begun to hone in on the key residues that were critical for the assembly of keratin intermediate filaments, but we couldn’t predict the disease we should be looking at from the disrupted keratin networks we saw in our cultured skin cells. We thought that engineering mice harboring our dominant-negative keratin gene might offer us better clues. We set up transgenic mouse technology, but when we got our mice expressing mutant keratin, they showed no phenotype at all. I thought, “We just wasted all this time learning this technology, and we’re getting nowhere.”

Then one day a technician said, “There’s this dead mouse that’s half eaten, and it looks like it’s got a severe problem with its skin.” We took a look and it was expressing whopping amounts of our transgene. We realized that the mom was eating every single phenotypic mutant while leaving behind all the nonphenotypic ones. I gave [laboratory members] Bob Vassar and Pierre Coulombe my office for the night, and they babysat until the moms delivered. After their preliminary analysis, we sat down with a dermatology textbook and it was pretty clear: the pathology matched perfectly with epidermolysis bullosa simplex, a blistering skin disorder in humans.

But not everyone believed you at first?

No. I don’t blame people because diagnosing mice as having a particular human disease was unconventional at the time. I presented the work at a large meeting, and the chair took the microphone and said, “I don’t know what you’ve got, but you certainly don’t have EBS.” It took a few moments for me to react—it was looking pretty bad. The audience listened to the chair, who continued to declare confidently that our findings were rubbish.“There’s this endless array of signals from the environment that encompasses almost every aspect of biology.”

But at that point Mina Bissell stood up and said, “I don’t know whether she’s going to be right or wrong, but I just heard an interesting story, and I think we should give her the chance to find out.” This broke the ice for UPenn’s chair of dermatology, John Stanley, to stand up and say, “Actually, I would also diagnose the pathology as EBS.” Eight months later, we published a paper documenting the human genetic basis of EBS, so it didn’t take long to prove our hypothesis.

You were one of very few female group leaders when you began in Chicago. How was that?

A technician from another laboratory came down as I was setting up my laboratory, and said, “Are you Dr. Fuchs’ new technician?” and I had to say, “I am Dr. Fuchs!” There were cases where I’d be introduced to the seminar speaker as the prettiest member of the department—things that would make me cringe. I didn’t know what to make of these comments, and I’m not sure the men knew what to make of having me there.

I didn’t care what my salary was—it was more than I’d got as a postdoc— until after I was a tenured faculty member, when I discovered that my salary was actually lower than what they were offering to starting assistant professors. It was only after I realized I’d been underpaid all those years that I got angry. So there were definitely gender issues that could’ve distracted me, but I was so thrilled to be able to do my science that nothing else seemed to matter so much.

You’ve been a strong advocate for women in science, which was recognized by your L’Oreál-UNESCO award. Do any significant challenges remain?

Things are enormously better, particularly in the US. In general, the door is open for women all the way up to being an associate professor but it’s still difficult at the upper end of the scale—there are very few women in leadership positions. And there are still women at some universities who feel they are underpaid, have less space, and receive fewer privileges than their male colleagues. Most major universities have gotten the message, but I’m not sure all the smaller universities have followed suit.

The other prize you won recently was the National Medal of Science. How was your trip to the White House?

Fuchs receives the National Medal of Science from President Obama.

SANDY SCHAEFFER/NSF

Having the President of the United States shake my hand and place a medal around my neck was a moving experience. It was also nice to have not only my husband, but also my mother (who’s close to 88 years old now), my sister, and eldest nephew present. It was particularly thrilling for me because President Obama recognizes the importance of basic research and science education to the future of our country.

Could scientists do a better job of communicating the importance of their work?

Yes—we need to educate politicians about the importance of basic research and increasing the budget for it. [Former congressman] John Porter, at a recent Howard Hughes meeting, asked us all, “When was the last time you contacted a politician and invited them to your laboratory? They need to see what scientists are doing.” If politicians don’t understand what we can learn from basic research and appreciate its importance, why should they support it?

How do you maintain your enthusiasm?

A professor’s role is a combination of research and education. I empathize with the pain students feel as they initially struggle with scientific research, yet there’s nothing more gratifying than watching a student’s first experiment work. You see them think, “Well, it’s really worth it after all. I can do it.” As long as I’m passionate about the scientific questions we tackle, I don’t think I’ll ever get tired of being a professor. It’s the best possible job in the world.

What can we expect next from the Fuchs laboratory?

New approaches, of course! We’ve identified lots of new genes that change their expression patterns as stem cells make epidermis and hair follicles. But we can’t use classical genetics to figure out what all these changes mean—a conditional knockout mouse takes a couple of years to make, and there’s a lot of redundancy in the genome. We’re developing new strategies to make functional analyses of mouse skin development a more tractable process. There are many signaling pathways that must converge to build and maintain tissues during normal development and wound repair, and a lot of pathways go awry to generate the myriad of human skin disorders, including cancers. We know a little bit here and there, yet we still have a lot of pieces to fill in. But I love the puzzle!

References

1. 1.↵
   1. Fuchs, E.,
   2. H. Green

   . 1978. Cell. 15:887–897.

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   1. Fuchs, E.,
   2. H. Green

   . 1980. Cell. 19:1033–1042.

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   1. Vassar, R.,
   2. et al

   . 1991. Cell. 64:365–380.

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   1. Coulombe, P.A.,
   2. et al

   . 1991. Cell. 66:1301–1311.

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   1. Gat, U.,
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   . 1998. Cell. 95:605–614.

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   1. Tumbar, T.,
   2. et al

   . 2004. Science. 303:359–363.

   Abstract/FREE Full Text
7. 7.↵
   1. Blanpain, C.,
   2. et al

   . 2004. Cell. 118:635–648.

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