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 deletion of the first of three repeats. This truncation correlates with efficient oncogenic transformation and a decrease in DNA-binding activity. Here we demonstrate that the D-type cyclins, cyclin D1 and D2 in particular, specifically inhibit transcription when activated through the v-Myb DNA-binding domain, but not the c-Myb DNA-binding domain. Analysis of a cyclin D1 mutant and a dominant-negative CDK4 mutant implied that this repression is independent of complex formation with a CDK partner. Association of cyclin D1 and D2 with the Myb DNA-binding domain could be demonstrated. Increased levels of cyclin D1 and D2 resulted in a stabilization of the Myb proteins, but not in an alteration in binding of the Myb proteins to DNA. These results highlight an unexpected 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 underlying the oncogenic activity of v-Myb, which appears to be a stronger transcriptional activator following the TPA-induced differentiation of transformed monoblasts when cyclin D1 and D2 are down-regulated.
Ganter
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Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324, USA.
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D000818:Animals; D002461:Cell Line, Transformed; D002645:Chickens; D019938:Cyclin D1 / Q000378:metabolism*; D056742:Cyclin D2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020626:Oncogene Proteins v-myb; D011485:Protein Binding; D015682:Retroviridae Proteins, Oncogenic / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation
C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D004268:DNA-Binding Proteins; D020626:Oncogene Proteins v-myb; D015682:Retroviridae Proteins, Oncogenic; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases