C-MYC INHIBITS MYOGENIC DIFFERENTIATION AND MYOD EXPRESSION BY A MECHANISM WHICH CAN BE DISSOCIATED FROM CELL-TRANSFORMATION

The c-Myc oncoprotein is a basic-helix-loop-helix-leucine zipper (b-HL H-LZ) transcription factor involved in regulating cell proliferation a nd differentiation. We have used retrovirus-mediated gene transfer to investigate the effect of ectopic c-Myc expression on the spontaneous differentiation of primary quail myoblasts in vitro. Unlike normal myo blasts, c-Myc-expressing myoblasts are unable to form myotubes or expr ess muscle-specific genes, such as myosin, and show severely reduced e xpression of the myogenic regulatory factors myoD, myogenin, and myf5. The c-Myc leucine zipper (LZ) motif is essential for the differentiat ion block since myoblasts expressing a mutant with a partial deletion of this region, c-Myc Delta 7, differentiate and express myoD family r egulators and muscle-specific genes normally. Remarkably, c-Myc Delta 7, like wild-type c-Myc, retains the capacity to transform the growth phenotype of myoblasts, and associates with the b-HLH-LZ Myc partner p rotein Max in transformed cells. We conclude that the block to myogeni c differentiation induced by c-Myc can be dissociated from cell transf ormation per se, and that this attribute correlates more closely with down-regulation of myoD family gene expression. These findings are dis cussed in the light of current models of Myc function.