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Control of myogenic differentiation by cellular oncogenes

M D Schneider1, E N Olson

  • 1Department of Medicine, Baylor College of Medicine, Methodist Hospital, Houston, TX 77030.

Molecular Neurobiology
|January 1, 1988
PubMed

Insights

Cellular oncogenes like src and ras inhibit muscle cell differentiation by blocking tissue-specific gene expression, independent of DNA synthesis. Down-regulation of c-myc is not required for myogenesis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Developmental Biology

Background:

  • Skeletal muscle differentiation (myogenesis) requires cell cycle exit and cessation of DNA synthesis.
  • Growth factors and serum components inhibit myogenesis via unknown intracellular pathways.
  • Cellular proto-oncogenes are known to mediate growth factor signaling for cell proliferation.

Purpose of the Study:

  • To investigate the role of cellular oncogenes in regulating tissue-specific gene expression during muscle cell development.
  • To test the hypothesis that oncogenes can regulate, rather than just promote proliferation, in differentiating myoblasts.
  • To elucidate the signaling mechanisms by which oncogenes impact myogenesis.

Main Methods:

  • Genetic modification of myoblasts with viral oncogenes, cellular homologs, and inducible chimeric oncogenes.
  • Analysis of endogenous cellular oncogene regulation during myogenesis.
  • Assessment of effects on cell cycle status, DNA synthesis, and expression of muscle-specific genes.

Main Results:

  • Down-regulation of c-myc is not essential for myogenesis; its inhibitory effects on differentiation depend on sustained proliferation.
  • Activated src and ras genes directly block myocyte differentiation through a mechanism independent of DNA synthesis.
  • These inhibitory effects are rapidly reversible and mimic those of inhibitory growth factors.

Conclusions:

  • Cellular oncogenes, particularly activated src and ras, can directly inhibit muscle differentiation.
  • The mechanism involves a pathway independent of DNA synthesis, suggesting regulation of tissue-specific gene expression.
  • Transforming growth factor-beta and ras proteins may share a common transacting transcriptional signal to inhibit diverse muscle-specific genes.

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