Reporter: Prabodh Kandala, PhD
The human body does a great job of generating new cells to replace dead ones but it is not perfect. Cells need to communicate with or signal to each other to decide when to generate new cells. Communication or signaling errors in cells lead to uncontrolled cell growth and are the basis of many cancers.
At The University of Texas Health Science Center at Houston (UTHealth) Medical School, scientists have made a key discovery in cell signaling that is relevant to the fight against melanoma skin cancer and certain other fast-spreading tumors.
The scientists report that they have discovered why a class of drug called BRaf inhibitors that are widely used to treat melanomas do not always work and most importantly how these drugs may potentially accelerate cancer growth in certain patients. Melanoma, according to the American Cancer Society, accounts for almost 9,000 deaths each year. The scientists’ research was published online ahead of the June 5 print issue of Current Biology, which is published by Cell Press.
“This information may aid the development of more effective anti-cancer drugs and better inform the choice of new combinations of drugs,” said John Hancock, M.B, B.Chir, Ph.D., the study’s senior author, John S. Dunn Distinguished University Chair in Physiology and Medicine, chairman of the Department of Integrative Biology and Pharmacology and interim director of the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases at the UTHealth Medical School.
Growth signals are transmitted from a cell’s surface to the nucleus by a chain of proteins that form a signaling pathway. The command for cells to divide to generate new cells is relayed by a chain of four proteins (Ras → BRaf → MEK → ERK). All cells have this pathway and it does an effective job of generating new cells most of time.
Problems happen when a mutation occurs in one of the first two proteins in the chain — both of which lock the signaling pathway in the “on” position. The good news is that doctors have drugs that block signaling from the second protein known as BRaf. These are the BRaf inhibitors, which are successful at treating melanomas with mutant BRaf proteins.
The not-so-good news is that doctors cannot block the signal from the first protein called Ras. Researchers therefore studiedin vivo what happens when BRaf inhibitors are applied to human cancer tissues with Ras mutations.
“Surprisingly recent studies found that BRaf inhibitors do not block signaling in melanoma cells with Ras mutations. In fact, the drugs actually enhance the abnormal signaling activity. Our work now describes the mechanism for this seemingly paradoxical enhanced signaling activity,” said Kwang-jin Cho, Ph.D., the study’s lead author and research fellow at the UTHealth Medical School.
Most melanomas isolated from patients turn out to have either a BRaf or Ras mutation but rarely have both. Ras mutations cause an otherwise normal BRaf protein to stay switched on.
“Our study also emphasizes the importance of genetic testing of melanomas before using BRaf inhibitors. Our study may also help design a better drug,” Cho said.
The study was supported by the Cancer Prevention & Research Institute of Texas.
Hancock and Cho’s co-authors from the UTHealth Medical School are: Jin-Hee Park, senior research assistant; Sravanthi Chigurupati, senior research assistant; Dharini van der Hoeven, Ph.D., research fellow; and Sarah J. Plowman, Ph.D., assistant professor.
Other collaborators include: Rinshi S. Kasai, Ph.D., and Akihiro Kusumi, Ph.D., Kyoto University, Japan; and Sonja J. Heidorn, Ph.D., and Richard Marais, Ph.D., Institute for Cancer Research, London.
http://www.sciencedaily.com/releases/2012/05/120510122853.htm
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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