Control of myogenic differentiation by cellular oncogenes.
The establishment of a differentiated phenotype in skeletal muscle cells requires withdrawal from the cell cycle and termination of DNA synthesis. Myogenesis can be inhibited by serum components, purified mitogens, and transforming growth factors, but the intracellular signaling pathways utilized by these molecules are unknown. Recent studies have confirmed a role for proteins encoded by cellular proto-oncogenes in transduction of growth factor effects that lead to cell proliferation. To test the contrasting hypothesis that cellular oncogenes might also regulate tissue-specific gene expression in developing muscle cells, myoblasts have been modified by incorporation of the cognate viral oncogenes, the corresponding normal or oncogenic cellular homologs, and chimeric oncogenes, whose expression can be induced reversibly. Regulation of the endogenous cellular oncogenes also has been examined in detail. Down-regulation of c-myc is not obligatory for myogenesis; rather, inhibitory effects of myc on muscle differentiation are contingent on sustained proliferation. In contrast, activated src and ras genes block myocyte differentiation directly, through a mechanism that is independent of DNA synthesis and is rapidly reversible, resembling the effects of inhibitory growth factors. The coordinate regulation of diverse tissue-specific gene products including muscle creatine kinase, nicotinic acetylcholine receptors, sarcomeric proteins, and voltage-gated ion channels, raises the hypothesis that inhibitors such as transforming growth factor-beta and ras proteins might exert their effects through a transacting transcriptional signal shared by multiple muscle-specific genes.
Schneider
M D
MD
Department of Medicine, Baylor College of Medicine, Methodist Hospital, Houston, TX 77030.
Olson
E N
EN
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D011905:Genes, ras / Q000502:physiology; D006133:Growth Substances / Q000502:physiology; D005810:Multigene Family / Q000502:physiology; D009132:Muscles / Q000166:cytology*; D009857:Oncogenes / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics
D006133:Growth Substances; D011505:Protein-Tyrosine Kinases