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Site-specific acetylation of p53 directs selective transcription complex assembly.

Abstract
Histone deacetylase (HDAC) inhibitors are being investigated as possible adjuvant therapies for a number of diseases, including cancer. In addition to stabilization of acetylated histones, HDAC inhibitors stabilize the acetylation of a number of transcription factors, including p53. This study investigates the action of two HDAC inhibitors, CG-1521 and trichostatin A, which stabilize Ac-Lys-373 p53 and Ac-Lys-382 p53, respectively, in LNCaP prostate cancer cells. Real-time PCR demonstrates that CG-1521 induces p21 transcription whereas trichostatin A does not alter the steady state level of p21 mRNA. Co-immunoprecipitation demonstrates that the selective acetylation of p53 directs the recruitment of mutually exclusive coactivator complexes on the p53 response elements in the p21 promoter. Furthermore, the co-activator complexes initiate the recruitment of the components of the basal transcription apparatus to the basal promoter with markedly different outcomes because only Ac-Lys-373 p53 promotes the assembly of the basal transcriptional apparatus on the p21 promoter. These data highlight the profound effects of post-translational modification, including acetylation, on the function of p53. The data also suggest a novel and critically important role for protein acetylation/deacetylation in the assembly of active transcription processes that may be as important as classical phosphorylation/dephosphorylation.
AuthorsSomdutta Roy, Martin Tenniswood
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 7 Pg. 4765-71 (Feb 16 2007) ISSN: 0021-9258 [Print] United States
PMID17121856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • RNA, Messenger
  • RNA, Neoplasm
  • Tumor Suppressor Protein p53
  • trichostatin A
  • Histone Deacetylases
Topics
  • Acetylation
  • Cell Line, Tumor
  • Chemotherapy, Adjuvant
  • Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis)
  • Enzyme Inhibitors (pharmacology)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases (metabolism)
  • Histones (metabolism)
  • Humans
  • Hydroxamic Acids (pharmacology)
  • Male
  • Promoter Regions, Genetic
  • Prostatic Neoplasms (drug therapy, metabolism)
  • Protein Processing, Post-Translational
  • RNA, Messenger (metabolism)
  • RNA, Neoplasm (metabolism)
  • Transcription, Genetic (drug effects)
  • Tumor Suppressor Protein p53 (metabolism)

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