Transcriptional down-regulation of myogenin expression is associated with v-ras-induced block of differentiation in unestablished quail muscle cells.

Unestablished quail myoblasts were infected with a retroviral vector encoding the oncogenic form of H-Ras in order to investigate the mechanism by which this oncoprotein interferes with terminal differentiation. Primary quail myogenic cells exhibit the simultaneous expression of the muscle regulatory genes myf-5, MyoD and myogenin in proliferative conditions. v-ras-transformed myoblasts displayed an altered growth control and lost the competence for terminal differentiation. When expression of myogenic regulatory genes was analysed, it was immediately apparent that the difference between normal and v-ras-transformed cells was limited to a severely decreased level of myogenin expression. Forced expression of exogenous myogenin in v-ras-transformed quail myoblasts led to a striking recovery of the competence for terminal differentiation. The present data show that: (i) repression of myogenin expression is linked to the differentiation defective phenotype of quail myoblasts transformed by v-ras as well as other retroviral oncogenes; (ii) correction of the differentiation-defective phenotype of v-ras-transformed myoblasts by exogenous myogenin entailed reactivation of endogenous myogenin and of the E-box-dependent transactivating function. These results strongly indicate that myogenin expression plays a central role in regulating the transition into the terminally differentiated state and that its transcriptional down-regulation represents a nodal step in v-ras-induced block of differentiation.