REPRESSION OF C-FOS PROMOTER BY MYOD ON MUSCLE-CELL DIFFERENTIATION

TERMINAL differentiation and cell proliferation are in many cases, as in muscle cells1, mutually exclusive processes. While differentiating myoblasts are withdrawn from the cell cycle2, myogenesis is inhibited by some mitogens and overexpression of some oncogenes3,4, including proto-oncogene c-fos5 (which expresses a growth-associated protein constituting the regulatory factor AP-1 in conjunction with c-Jun6,7). MyoD, a muscle-specific transcription factor of the basic helix-loop-helix family8,9, acts at both levels because it triggers a muscle differentiation programme in non-muscle cells10-12, and induces a complete block of cell proliferation13,14. Antagonistic interaction between MyoD and c-Jun has been demonstrated15. We here show that c-fos expression greatly decreases upon muscle cell differentiation, concomitant with MyoD-induced activity. We have identified a MyoD-binding site overlapping with the serum-responsive element in the c-fos promoter. We demonstrate that MyoD can act as a negative regulator for c-fos transcription by blocking serum responsiveness through this binding site. These data suggest that the MyoD negative effect on cell growth could be partly mediated by transcriptional inactivation of growth-responsive genes.