Cyclin A is a functional target of retinoblastoma tumor suppressor protein-mediated cell cycle arrest

Karen E. Knudsen, Anne F. Fribourg, Matthew W. Strobeck, Jean Marie Blanchard, Erik S. Knudsen

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Although RB inhibits the G(i)-S transition, the mechanism through which RB prevents cell cycle advancement remains unidentified. To delineate the mechanism(s) utilized by RB to exert its anti-proliferative activity, constitutively active RB proteins (which cannot be inactivated by phosphorylation) or p16ink4a (which prevents RB inactivation) were utilized. Both proteins inhibited the G1-S transition, whereas wild-type RB did not. We show that active RB acts to attenuate cyclin A promoter activity, and that overexpression of cyclin E reverses RB-mediated repression of the cyclin A promoter. Although cyclin A is an E2F-regulated gene, and it has been long hypothesized that RB mediates cell cycle advancement through binding to E2F and attenuating its transactivation potential, cyclin E does not reverse dominant negative E2F-mediated repression of the cyclin A promoter. Although active RB repressed both cyclin A and two other paradigm E2F-regulated promoters, only cyclin A transcription was restored upon co-expression of cyclin E. Additionally, we show that RB but not dominant negative E2F regulates the cyclin A promoter through the CCRE element. These data identify cyclin A as a downstream target of RB-mediated arrest. Consistent with this idea, ectopic expression of cyclin A reversed RB-mediated G1 arrest. The findings presented suggest a pathway wherein cyclin A is a downstream target of RB, and cyclin E functions to antagonize this aspect of RB-mediated G1-S inhibition.

Original languageEnglish (US)
Pages (from-to)27632-27641
Number of pages10
JournalJournal of Biological Chemistry
Volume274
Issue number39
DOIs
StatePublished - Sep 24 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Knudsen, K. E., Fribourg, A. F., Strobeck, M. W., Blanchard, J. M., & Knudsen, E. S. (1999). Cyclin A is a functional target of retinoblastoma tumor suppressor protein-mediated cell cycle arrest. Journal of Biological Chemistry, 274(39), 27632-27641. https://doi.org/10.1074/jbc.274.39.27632