Document Detail


p27Kip1 induces an accumulation of the repressor complexes of E2F and inhibits expression of the E2F-regulated genes.
MedLine Citation:
PMID:  9307976     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
p27Kip1 is an inhibitor of the cyclin-dependent kinases and it plays an inhibitory role in the progression of cell cycle through G1 phase. To investigate the mechanism of cell cycle inhibition by p27Kip1, we constructed a cell line that inducibly expresses p27Kip1 upon addition of isopropyl-1-thio-beta-D-galactopyranoside in the culture medium. Isopropyl-1-thio-beta-D-galactopyranoside-induced expression of p27Kip1 in these cells causes a specific reduction in the expression of the E2F-regulated genes such as cyclin E, cyclin A, and dihydrofolate reductase. The reduction in the expression of these genes correlates with the p27Kip1-induced accumulation of the repressor complexes of the E2F family of factors (E2Fs). Our previous studies indicated that p21WAF1 could disrupt the interaction between cyclin/cyclin-dependent kinase 2 (cdk2) and the E2F repressor complexes E2F-p130 and E2F-p107. We show that p27Kip1, like p21WAF1, disrupts cyclin/cdk2-containing complexes of E2F-p130 leading to the accumulation of the E2F-p130 complexes, which is found in growth-arrested cells. In transient transfection assays, expression of p27Kip1 specifically inhibits transcription of a promoter containing E2F-binding sites. Mutants of p27Kip1 harboring changes in the cyclin- and cdk2-binding motifs are deficient in inhibiting transcription from the E2F sites containing reporter gene. Moreover, these mutants of p27Kip1 are also impaired in disrupting the interaction between cyclin/cdk2 and the repressor complexes of E2Fs. Taken together, these observations suggest that p27Kip1 reduces expression of the E2F-regulated genes by generating repressor complexes of E2Fs. Furthermore, the results also demonstrate that p27Kip1 inhibits expression of cyclin A and cyclin E, which are critical for progression through the G1-S phases.
Authors:
P Shiyanov; S Hayes; N Chen; D G Pestov; L F Lau; P Raychaudhuri
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular biology of the cell     Volume:  8     ISSN:  1059-1524     ISO Abbreviation:  Mol. Biol. Cell     Publication Date:  1997 Sep 
Date Detail:
Created Date:  1997-12-04     Completed Date:  1997-12-04     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9201390     Medline TA:  Mol Biol Cell     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1815-27     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, University of Illinois at Chicago 60612, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Carrier Proteins*
Cell Culture Techniques / methods
Cell Cycle Proteins*
Cell Line
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases / antagonists & inhibitors
DNA-Binding Proteins*
E2F Transcription Factors
Gene Expression Regulation / drug effects
Genes, Tumor Suppressor
Mice
Microtubule-Associated Proteins / biosynthesis,  physiology*
Retinoblastoma-Binding Protein 1
Transcription Factor DP1
Transcription Factors / antagonists & inhibitors*,  genetics,  metabolism*
Tumor Suppressor Proteins*
Grant Support
ID/Acronym/Agency:
CA-52220/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Arid4a protein, mouse; 0/Carrier Proteins; 0/Cdkn1b protein, mouse; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/E2F Transcription Factors; 0/Microtubule-Associated Proteins; 0/Retinoblastoma-Binding Protein 1; 0/Transcription Factor DP1; 0/Transcription Factors; 0/Tumor Suppressor Proteins; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; EC 2.7.11.22/Cyclin-Dependent Kinases
Comments/Corrections

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