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Posts Tagged ‘RNA-binding protein’


Reprogramming Cell in Tissue Repair

Reporter and Curator: Larry H Bernstein, MD, FCAP

This is a novel concept in regenerative medicine that needs attention.

Lin28 enhances tissue repair by reprogramming cellular metabolism

Shyh-Chang N, Zhu H, Yvanka de Soysa T, Shinoda G, Seligson M T, Tsanov K M, Nguyen L, Asara J M, Cantley L C and Daley G Q.

Stem Cell Transplantation Program,Boston Children’s Hospital and Dana Farber Cancer Institute, Boston; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; Harvard Stem Cell Institute;
Manton Center for Orphan Disease Research; Howard Hughes Medical Institute; Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115.

Cell.  7 Nov 2013; 155(4):778-792.    http://dx.doi.org/10.1016/j.cell.2013.09.059.

Lin28 overview

Copyright © 2013 Elsevier Inc.  PMID:     23561442     PMCID:     PMC3652335

Abstract

In recent years, the highly conserved Lin28 RNA-binding proteins have emerged as factors that define stemness in several tissue lineages. Lin28 proteins repress let-7 microRNAs and influence mRNA translation, thereby regulating the self-renewal of mammalian embryonic stem cells. Subsequent discoveries revealed that Lin28a and Lin28b are also important in organismal growth and metabolism, tissue development, somatic reprogramming, and cancer. In this review, we discuss the Lin28 pathway and its regulation, outline its roles in stem cells, tissue development, and pathogenesis, and examine the ramifications for re-engineering mammalian physiology.

Figure 1. Overview of Molecular Mechanisms Underlying Lin28 Function. From: Lin28: Primal Regulator of Growth and Metabolism in Stem Cells.

nihms459462f1  stem cells Lin28

Both Lin28a and Lin28b have been observed to shuttle between the nucleus and cytoplasm, binding both mRNAs and pri-/prelet-7. In the nucleus, Lin28a/b could potentially work in tandem with the heterogeneous nuclear ribonucleoproteins (hnRNPs) to regulate splicing, or with Musashi-1 (Msi1) to block pri-let-7 processing. In the cytoplasm, Lin28a recruits Tut4/7 to oligouridylate pre-let-7, and block Dicer processing to mature let-7 miRNA (right, violet). Lin28a also recruits RNA helicase A (RHA) to regulate mRNA processing in messenger ribonucleoprotein (mRNP) complexes, in tandem with the Igf2bp’s, poly(A)-binding protein (PABP), and the eukaryotic translation initiation factors (eIFs). In response to unknown signals and stimuli, the mRNAs are either shuttled into poly-ribosomes for translation, stress granules for temporary sequestering, or P-bodies for degradation, in part via miRNAs and the Ago2 endonuclease (left, orange).

Figure 2. Signals Upstream and Targets Downstream of Lin28 in the Lin28 Pathway. From: Lin28: Primal Regulator of Growth and Metabolism in Stem Cells.

nihms459462f2  Linm28 stem cell signals

The lin-4 homolog miR-125a/b represses both Lin28a and Lin28b during stem cell differentiation. The core pluripotency transcription factors Oct4, Sox2, Nanog and Tcf3 can activate Lin28a transcription in ESCs and iPSCs, whereas the growth regulator Myc and the inflammation-/stress-responsive NF-κB can transactivate Lin28b. A putative steroid hormone-activated nuclear receptor, conserved from C. elegans daf-12, might also regulate both Lin28a/b and let-7 expression. Downstream of Lin28a/b, the let-7 family represses a network of proto-oncogenes, including the insulin-PI3K-mTOR pathway, Ras, Myc, Hmga2, and the Igf2bp’s. At the same time, Lin28a can also directly bind to and regulate translation of mRNAs, including Igf2bp’s, Igf2, Hmga1, and mRNAs encoding metabolic enzymes, ribosomal peptides, and cell-cycle regulators. Together, this broad network of targets allows Lin28 to program both metabolism and growth to regulate self-renewal.

Figure 3. Potential of Lin28 in Re-Engineering Adult Mammalian Physiology. From: Lin28: Primal Regulator of Growth and Metabolism in Stem Cells.

nihms459462f3  stem cell Lin28

Lin28a, in conjunction with the pluripotency factors Oct4, Sox2 and Nanog, can reprogram somatic cells into iPSCs. Alone, Lin28a/b can reprogram adult HSPCs into a fetal-like state, and enhance insulin sensitivity in the skeletal muscles to improve glucose homeostasis, resist obesity and prevent diabetes. Emergent clues suggest that optimal doses of Lin28a/b might have the potential to re-engineer adult mammalian tissue repair capacities and extend longevity, although Lin28a/b could also cooperate with oncogenes to initiate tumorigenesis. Future work might elucidate these mysteries.

Cell. 2013 Nov 7;155(4):778-92. doi: 10.1016/j.cell.2013.09.059.

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Curated by: Dr. Venkat S. Karra, Ph.D

Auguste Deter. Alois Alzheimer's patient in No...

Nuerodegenertive disease – Alzheimer’s – is presumed to be caused by the accumulation of β-amyloid.

The diagnosis of Alzheimer’s disease focuses on

β-amyloid protein and

tau protein

Though much attention is on radiolabeled markers, imaging βamyloid is problematic because many cognitively normal elderly have large amounts of β-amyloid in their brain, and appear as “positives” in the imaging tests.

At the same time therapeutic approaches for Alzheimer’s disease have not been focused much on the process of producing a neurofibrillary tangle composed on tau protein.

Various brain sections showing tau protein

Various brain sections showing tau protein (Photo credit: WBUR)

Now the BUSM researchers identified a new group of proteins, termed RNA-binding proteins, which accumulate in the brains of patients with Alzheimer’s disease, and are present at much lower levels in subjects who are cognitively intact.

The researchers believe this work opens up novel approaches to diagnose and stage the likelihood of progression by quantifying the levels of these RNA-binding protein biomarkers that accumulate in the brains of Alzheimer patients.

The group found two different proteins, both of which show striking patterns of accumulation. “Proteins such as TIA-1 and TTP, accumulate in neurons that accumulate tau protein, and co-localize with neurofibrillary tangles. These proteins also bind to tau, and so might participate in the disease process,” explained senior author Benjamin Wolozin, MD, PhD, a professor in the departments of pharmacology and neurology at BUSM.

“A different RNA binding protein, G3BP, accumulates primarily in neurons that do not accumulate pathological tau protein.

This observation is striking because it shows that neurons lacking tau aggregates (and neurofibrillary tangles) are also affected by the disease process,” he added.

Wolozin’s group also pursued the observation that some of the RNA binding proteins bind to tau protein, and tested whether one of these proteins, TIA-1, might contribute to the disease process.

‘Stress’ induced aggregation of RNA-binding proteins

Previously, scientists like Tara Vanderweyde et. al., have demonstrated that TIA-1 spontaneously aggregates in response to stress as a normal part of the stress response. They examined the relationship between Stress Granules (SGs) and neuropathology in brain tissue from P301L Tau transgenic mice, as well as in cases of Alzheimer’s disease and FTDP-17.

Stress Granules (SGs) are ‘Stress’ induced aggregation of RNA-binding proteins.

The pattern of SG pathology differed dramatically based on the RNA-binding protein examined. SGs positive for T-cell intracellular antigen-1 (TIA-1) or tristetraprolin (TTP) initially did not co-localize with tau pathology, but then merge with tau inclusions as disease severity increases. In contrast, G3BP (ras GAP-binding protein) identifies a novel type of molecular pathology that shows increasing accumulation in neurons with increasing disease severity, but often is not associated with classic markers of tau pathology. TIA-1 and TTP both bind phospho-tau, and TIA-1 overexpression induces formation of inclusions containing phospho-tau. These data suggest that SG formation might stimulate tau pathophysiology.

Thus, study of RNA-binding proteins and SG biology highlights novel pathways interacting with the pathophysiology of AD.

With this understanding, Wolozin and his colleagues hypothesize that since TIA-1 binds tau, it might stimulate tau aggregation during the stress response. They introduced TIA-1 into neurons with tau protein, and subjected the neurons to stress. Consistent with their hypothesis, tau spontaneously aggregated in the presence of TIA-1, but not in the absence. Thus, the group has potentially identified an entirely novel mechanism to induce tau aggregates de novo.

In future work, the group hopes to use this novel finding to understand how neurofibrillary tangles for in Alzheimer’s disease and to screen for novel compounds that might inhibit the progression of Alzheimer’s disease.

They believe that it may open up novel approaches to diagnose and stage the progression likelihood of the disease in Alzheimer patients.

Curated by: Dr. Venkat S. Karra, Ph.D

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