Document Detail


Mitogenic regulation of p27(Kip1) gene is mediated by AP-1 transcription factors.
MedLine Citation:
PMID:  19959471     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The abundance of cyclin-dependent kinase inhibitor p27(Kip1) during the cell cycle determines whether cells will proliferate or become quiescent. Although the post-translational regulation of p27(Kip1) is well established, its transcriptional regulation is poorly understood. Here, we report that mitogenic stimulation of quiescent HEK293 and Huh7 cells showed a rapid decline in the levels of p27(Kip1) transcript by 2.4 +/- 0.1-fold. Inhibition of the p27(Kip1) gene in response to mitogens involved transcriptional down-regulation and required newly synthesized protein(s). Mutation of the AP-1 element at position -469 in the human p27(Kip1) promoter abrogated the effect of mitogens. The recruitment of the AP-1 complex to the p27(Kip1) promoter was confirmed by in vitro DNA binding and chromatin immunoprecipitation studies. Reporter gene analysis combined with enforced expression of Jun/Fos proteins suggested the involvement of Jun/Fos heterodimer in the transrepression process. Both MAPK and phosphatidylinositol 3-kinase signaling pathways appeared to mediate p27(Kip1) transcription. Furthermore, hepatitis B virus X protein-mediated down-regulation of p27(Kip1) in a transgenic environment correlated with an increase in c-Fos levels, reiterating the physiological relevance of AP-1 in the transcriptional regulation of p27(Kip1). Collectively, our studies present the first evidence demonstrating the role of the AP-1 complex in transcriptional down-regulation of the p27(Kip1) gene following mitogenic stimulation.
Authors:
Ekta Khattar; Vijay Kumar
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-12-02
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-08     Completed Date:  2010-05-11     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4554-61     Citation Subset:  IM    
Affiliation:
Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
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MeSH Terms
Descriptor/Qualifier:
Blotting, Western
Cell Line
Cell Line, Tumor
Chromatin Immunoprecipitation
Chromones / pharmacology
Computational Biology
Cyclin-Dependent Kinase Inhibitor p27 / genetics,  metabolism*
Electrophoretic Mobility Shift Assay
Flavonoids / pharmacology
Flow Cytometry
Humans
MAP Kinase Kinase 1 / antagonists & inhibitors,  metabolism
Morpholines / pharmacology
Phosphatidylinositol 3-Kinases / antagonists & inhibitors,  metabolism
Polymerase Chain Reaction
Promoter Regions, Genetic / genetics,  physiology
Protein Multimerization / genetics,  physiology
Proto-Oncogene Proteins c-fos / genetics,  metabolism
Proto-Oncogene Proteins c-jun / genetics,  metabolism
RNA, Small Interfering / genetics,  physiology
Signal Transduction / drug effects,  genetics
Tetradecanoylphorbol Acetate / pharmacology
Transcription Factor AP-1 / genetics,  physiology*
Chemical
Reg. No./Substance:
0/2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; 0/Chromones; 0/Flavonoids; 0/Morpholines; 0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-jun; 0/RNA, Small Interfering; 0/Transcription Factor AP-1; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 16561-29-8/Tetradecanoylphorbol Acetate; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.12.2/MAP Kinase Kinase 1
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