Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myogenic differentiation can be inhibited by the adenovirus E1a protein in the rat L6 muscle cell line. The present investigation provides evidence that E1a interferes with the expression of myogenin and the activity of Myf-5, the two myogenic helix-loop-helix (HLH) proteins that are expressed in L6 muscle cells. In nuclei of E1a-expressing L6 cells, Myf-5 protein accumulates to normal or even elevated levels and shows no alterations of its ability to bind to the DNA-binding site (CANNTG). However, trans-activation of muscle-specific reporter genes by Myf-5 is strongly inhibited. The same inhibition by E1a can be shown for the other myogenic HLH proteins, MyoD, myogenin, and MRF4/Myf-6, that have been expressed in 10T1/2 fibroblasts. In contrast to the normal level of Myf-5 expression, synthesis of myogenin is entirely abolished in the differentiation-defective L6-E1a cells. Here, we demonstrate that the carboxy-terminal trans-activator domain and probably the basic-HLH (bHLH) region of Myf-5 constitute targets for the inhibition by E1a. The effect of E1a depends on its intact transforming regions but not on the transcriptional activator domain. Our data suggest that activation of myogenin gene expression and the establishment of the differentiated phenotype may require functional Myf-5. Expression of the Myf-5 gene, however, is apparently independent of auto- or cross-regulation by the myogenic HLH proteins.
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PMID:Inhibition of muscle differentiation by the adenovirus E1a protein: repression of the transcriptional activating function of the HLH protein Myf-5. 131 6

A major control point for skeletal myogenesis revolves around the muscle basic helix-loop-helix gene family that includes MyoD, Myf-5, myogenin, and MRF4. Myogenin and MRF4 are thought to be essential to terminal differentiation events, whereas MyoD and Myf-5 are critical to establishing the myogenic cell lineage and producing committed, undifferentiated myogenic stem cells (myoblasts). Although mouse genetic studies have revealed the importance of MyoD and Myf-5 for myoblast development, the genetic targets of MyoD and Myf-5 activity in undifferentiated myoblasts remain unknown. In this study, we investigated the function of MyoD as a transcriptional activator in undifferentiated myoblasts. By using conditional expression of MyoD, in conjunction with suppression subtractive hybridizations, we show that the Id3 and NP1 (neuronal pentraxin 1) genes become transcriptionally active following MyoD induction in undifferentiated myoblasts. Activation of Id3 and NP1 represents a stable, heritable event that does not rely on continued MyoD activity and is not subject to negative regulation by an activated H-Ras G12V protein. These results are the first to demonstrate that MyoD functions as a transcriptional activator in myogenic stem cells and that this key myogenic regulatory factor exhibits different gene target specificities, depending upon the cellular environment.
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PMID:Identification of novel MyoD gene targets in proliferating myogenic stem cells. 1216 13

The basic helix-loop-helix myogenic regulatory factors play critical roles in skeletal myogenesis. Among the myogenic regulatory factors (MRFs), MRF4 shows a biphasic expression pattern during the formation of myotomes, although its function remains unclear. In this study, we used BEF (spontaneously immortalized bovine embryonic fibroblast that shows myogenic differentiation by overexpression of MyoD) and C2C12 cells to investigate the function of MRF4. Ectopic expressions of MRF4 did not stimulate myogenic differentiation in the BEF and C2C12 cells, but did show a marked increase of cell proliferation, upregulation of cyclin E, and downregulation of p21WAF1. Furthermore, MRF4 was found to induce degradation of the MyoD protein, which acts as a transcriptional activator for p21WAF1, and thus indicates that MRF4 accelerates cell proliferation by suppressing MyoD-dependent p21WAF1 expression. However, forced expression of MyoD in the MRF4-overexpressing cells inhibited cell proliferation and partially induced myogenic differentiation, which suggests that MyoD is a potential negative intercessor of MRF4 in the regulation of the cell cycle. Taken together, these results indicate that MRF4 and MyoD play competitive roles in myogenesis by stimulating cell proliferation and differentiation, respectively.
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PMID:Opposite roles of MRF4 and MyoD in cell proliferation and myogenic differentiation. 1795 44