B-myb repressor function is regulated by cyclin a phosphorylation and sequences within the c-terminal domain

Constantinos Petrovas, Sébastien Jeay, Robert E. Lewis, Gail E. Sonenshein

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

B-Myb is a widely expressed member of the myb oncogene family that has been shown to act as either an activator or repressor of gene transcription in a cell-type-specific fashion. For example, in aortic smooth muscle cells B-Myb represses transcription of the α2(V) collagen gene. Recently, phosphorylation of B-Myb by cyclin A was shown to enhance greatly its ability to transactivate. Here, we have tested the effects of cyclin A on the ability of B-Myb to repress. We report that coexpression of cyclin A abolished repression of the α2(V) collagen promoter, whereas a dominant-negative cyclin-dependent kinase 2 (cdk2) enhanced repression by ectopic and endogenous B-Myb protein. Mutation of 10 of 22 putative cyclin A sites, which greatly reduces the effects of cyclin A on transactivation by B-Myb, had no effect on the ability of cyclin A to alleviate B-Myb-mediated repression of α2(V) collagen promoter activity. Furthermore, the stability of the mutant B-Myb protein was largely unaffected by cyclin A, although ectopic expression of cyclin A enhanced the rate of decay of wild-type B-Myb protein. Thus, the mechanisms of repression and activation appear distinct, for example, mediated by different critical phosphorylation sites or protein-protein interactions. B-Myb mutants with either deletion of aa 374-581 (B-Myb-Mut3) or C-terminal truncation beyond aa 491 (B-Myb-491) positively regulated α2(V) collagen promoter activity, and were not affected by cyclin A. Thus, our findings indicate that the ability of B-Myb to function as a repressor of matrix promoter activity is abolished by cyclin A, and maps the sites mediating negative regulation by B-Myb to the region between aa 491 and 582.

Original languageEnglish (US)
Pages (from-to)2011-2020
Number of pages10
JournalOncogene
Volume22
Issue number13
DOIs
StatePublished - Apr 3 2003

Keywords

  • B-myb oncogene
  • Cyclin A
  • Gene repression
  • Smooth muscle cells
  • Type V collagen

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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