Role of the Histone Acetyl Transferase Tip60 in the p53 Pathway

• Published in: The Journal of biological chemistry Vol. 279; no. 43; pp. 44825 - 44833
• Main Authors: Legube, Gaëlle, Linares, Laetitia K, Tyteca, Sandrine, Caron, Cécile, Scheffner, Martin, Chevillard-Briet, Martine, Trouche, Didier
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 22.10.2004
• Subjects: Acetyltransferases - physiology; Blotting, Western; Bromodeoxyuridine - pharmacology; Cell Cycle; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Dactinomycin - pharmacology; DNA Damage; Glutathione Transferase - metabolism; HeLa Cells; Histone Acetyltransferases; Humans; Immunoprecipitation; Lysine Acetyltransferase 5; Microscopy, Fluorescence; Nuclear Proteins - metabolism; Nucleic Acid Synthesis Inhibitors - pharmacology; Plasmids - metabolism; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-mdm2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - metabolism; Transfection; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - physiology; Ubiquitin - metabolism; Ultraviolet Rays
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M407478200

The histone acetyl transferase Tip60 (HTATIP) shares many properties with the tumor suppressor p53 (TP53). Both proteins are involved in the cellular response to DNA damage, are subjected to proteasomal digestion following Mdm2-mediated ubiquitination, and accumulate after UV irradiation. We found here that knock-down of Tip60 affects the p53-dependent response following actinomycin D treatment, most likely because it inhibits p21 (CDKN1A) accumulation. Moreover, Tip60 is required for p53 to activate the endogenous p21 promoter, suggesting that it functions as a p53 co-activator. However, we also found that knock-down of Tip60 increases the turnover rate of p53 under normal growth conditions. Tip60 interferes with Mdm2-mediated degradation of p53, probably because it affects its subcellular localization. Taken together, our results suggest that Tip60 plays a double role in the p53 pathway: under normal growth conditions, Tip60 contributes to maintain a basal pool of p53 by interfering with its degradation; following DNA damage, Tip60 functions as p53 co-activator. That these two distinct roles are linked during the p53-dependent response is an attractive hypothesis.