Document Detail

Histone deacetylase inhibitor activates the WAF1/Cip1 gene promoter through the Sp1 sites.
MedLine Citation:
PMID:  9405248     Owner:  NLM     Status:  MEDLINE    
Treatment of cultured cells with trichostatin A (TSA), a specific histone deacetylase inhibitor, induces the histone hyperacetylation and modulates expression of some mammalian genes. We examined the effects of TSA on cell growth arrest, and its relation to expression of the WAF1/Cip1 gene, a potent inhibitor of cyclin-dependent kinases, in a p53-mutated human osteosarcoma cell line MG63. TSA at 500 ng/ml induced growth arrest at both G1 and G2/M phases, and the expressions of the WAF1/Cip1 mRNA and protein. We also examined the changes of acetylated isoforms of histone H4. Dose-response and kinetic analysis suggest a close correlation between the level of histone acetylation and the induction of the WAF1/Cip1 expressions. Using several mutant WAF1/Cip1 promoter fragments, we found that the TSA responsive elements are two Sp1 sites at -82 and -69 relative to the transcription start site. These findings indicate that TSA induces the WAF1/Cip1 promoter through the typical Sp1 sites, in a p53-independent fashion. Furthermore, the Sp1-luc plasmid, containing SV40 promoter-derived three consensus Sp1 binding sites, was markedly activated by TSA, compared to the mutant Sp1-luc plasmid. These results demonstrate that transcriptional activation through the Sp1 sites of the WAF1/Cip1 promoter by TSA coincides with induced hyperacetylation of histone H4.
Y Sowa; T Orita; S Minamikawa; K Nakano; T Mizuno; H Nomura; T Sakai
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  241     ISSN:  0006-291X     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  1997 Dec 
Date Detail:
Created Date:  1998-01-15     Completed Date:  1998-01-15     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  142-50     Citation Subset:  IM    
Copyright Information:
Copyright 1997 Academic Press.
Department of Preventive Medicine, Second Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, 602, Japan.
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MeSH Terms
Binding Sites
Cell Cycle / drug effects
Cell Division / drug effects
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / biosynthesis*,  genetics
Enzyme Inhibitors / pharmacology*
Gene Expression Regulation / drug effects
Histone Deacetylase Inhibitors
Hydroxamic Acids / pharmacology*
Luciferases / biosynthesis
Promoter Regions, Genetic / drug effects*
RNA, Messenger / biosynthesis
Recombinant Fusion Proteins / biosynthesis
Sp1 Transcription Factor / metabolism*
Transcription, Genetic / drug effects
Tumor Cells, Cultured
Reg. No./Substance:
0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Enzyme Inhibitors; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/RNA, Messenger; 0/Recombinant Fusion Proteins; 0/Sp1 Transcription Factor; 58880-19-6/trichostatin A; EC 1.13.12.-/Luciferases

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