D-TYPE CYCLINS REPRESS TRANSCRIPTIONAL ACTIVATION BY THE V-MYB BUT NOT THE C-MYB DNA-BINDING DOMAIN

The v-Myb DNA-binding domain differs from that of c-Myb mainly by dele tion of the first of three repeats, This truncation correlates,vith ef ficient oncogenic transformation and a decrease in DNA-binding activit y, Here me demonstrate that the D-type cyclins, cyclin D1 and D2 in pa rticular, specifically inhibit transcription when activated through th e v-Myb DNA-binding domain, but not the c-Myb DNA-binding domain. Anal ysis of a cyclin D1 mutant and a dominant-negative CDK4 mutant implied that this repression is independent of complex formation with a CDK p artner, Association of cyclin D1 and D2 with the Myb DNA-binding domai n could be demonstrated. Increased levels of cyclin DI and D2 resulted in a stabilization of the Myb proteins, but not in an alteration in b inding of the Myb proteins to DNA, These results highlight an unexpect ed role for cyclin D as a CDK-independent repressor of transcriptional activation by v-Myb but not c-Myb, This differential effect of D-type cyclins on v-Myb and c-Myb might help to explain the mechanism underl ying the oncogenic activity of v-Myb, which appears to be a stronger t ranscriptional activator following the TPA-induced differentiation of transformed monoblasts when cyclin D1 and D2 are downregulated.