Document Detail


Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1).
MedLine Citation:
PMID:  16537920     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Generally, histone deacetylase (HDAC) inhibitor-induced p21(Waf1/Cip1) expression is thought to be p53 independent. Here we found that an inhibitor of HDAC, depsipeptide (FR901228), but not trichostatin A (TSA), induces p21(Waf1/Cip1) expression through both p53 and Sp1/Sp3 pathways in A549 cells (which retain wild-type p53). This is demonstrated by measuring relative luciferase activities of p21 promoter constructs with p53 or Sp1 binding site mutagenesis and was further confirmed by transfection of wild-type p53 into H1299 cells (p53 null). That p53 was acetylated after depsipeptide treatment was tested by sequential immunoprecipitation/Western immunoblot analysis with anti-acetylated lysines and anti-p53 antibodies. The acetylated p53 has a longer half-life due to a significant decrease in p53 ubiquitination. Further study using site-specific antiacetyllysine antibodies and transfection of mutated p53 vectors (K319/K320/K321R mutated and K373R/K382R mutations) into H1299 cells revealed that depsipeptide specifically induces p53 acetylation at K373/K382, but not at K320. As assayed by coimmunoprecipitation, the K373/K382 acetylation is accompanied by a recruitment of p300, but neither CREB-binding protein (CBP) nor p300/CBP-associated factor (PCAF), to the p53 C terminus. Furthermore, activity associated with the binding of the acetylated p53 at K373/K382 to the p21 promoter as well as p21(Waf1/Cip1) expression is significantly increased after depsipeptide treatment, as tested by chromatin immunoprecipitations and Western blotting, respectively. In addition, p53 acetylation at K373/K382 is confirmed to be required for recruitment of p300 to the p21 promoter, and the depsipeptide-induced p53 acetylation at K373/K382 is unlikely to be dependent on p53 phosphorylation at Ser15, Ser20, and Ser392 sites. Our data suggest that p53 acetylation at K373/K382 plays an important role in depsipeptide-induced p21(Waf1/Cip1) expression.
Authors:
Ying Zhao; Shaoli Lu; Lipeng Wu; Guolin Chai; Haiying Wang; Yingqi Chen; Jia Sun; Yu Yu; Wen Zhou; Quanhui Zheng; Mian Wu; Gregory A Otterson; Wei-Guo Zhu
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Molecular and cellular biology     Volume:  26     ISSN:  0270-7306     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2006 Apr 
Date Detail:
Created Date:  2006-03-15     Completed Date:  2006-04-24     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2782-90     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, #38 Xueyuan Road, Beijing 100083, China.
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MeSH Terms
Descriptor/Qualifier:
Acetylation / drug effects
Cyclin-Dependent Kinase Inhibitor p21 / genetics,  metabolism*
Depsipeptides / pharmacology*
Dose-Response Relationship, Drug
Gene Expression Regulation / drug effects*
Half-Life
Histone Deacetylase Inhibitors*
Humans
Lysine / metabolism*
Phosphorylation
Promoter Regions, Genetic / genetics
Protein Processing, Post-Translational
RNA, Messenger / genetics,  metabolism
Serine / metabolism
Sp1 Transcription Factor / metabolism
Time Factors
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / genetics,  metabolism*
p300-CBP Transcription Factors / metabolism
Chemical
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p21; 0/Depsipeptides; 0/Histone Deacetylase Inhibitors; 0/RNA, Messenger; 0/Sp1 Transcription Factor; 0/Tumor Suppressor Protein p53; 128517-07-7/romidepsin; 56-45-1/Serine; 56-87-1/Lysine; EC 2.3.1.48/p300-CBP Transcription Factors
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