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Cyclin A is a functional target of retinoblastoma tumor suppressor protein-mediated cell cycle arrest.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 1999 Sep 24; Vol. 274 (39), pp. 27632-41. - Publication Year :
- 1999
-
Abstract
- Although RB inhibits the G(1)-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 G(1)-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 G(1) 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 G(1)-S inhibition.
- Subjects :
- Animals
Cell Division
Cell Line
Cyclin A physiology
Cyclin E genetics
Cyclin E physiology
Cyclin-Dependent Kinase Inhibitor p16 metabolism
E2F Transcription Factors
G1 Phase
Gene Expression Regulation
Genes, Reporter
Luciferases genetics
Promoter Regions, Genetic
Recombinant Fusion Proteins biosynthesis
Retinoblastoma-Binding Protein 1
S Phase
Tetrahydrofolate Dehydrogenase genetics
Transcription Factors metabolism
Transfection
Carrier Proteins
Cell Cycle physiology
Cell Cycle Proteins
Cyclin A genetics
DNA-Binding Proteins
Retinoblastoma Protein physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 274
- Issue :
- 39
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 10488103
- Full Text :
- https://doi.org/10.1074/jbc.274.39.27632