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.

• Authors: Somdutta Roy, Martin Tenniswood
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 7 Pg. 4765-4771 (Feb 16 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17121856 (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)