title: Phosphorylation of Tip60 by p38α regulates p53-mediated PUMA induction and apoptosis in response to DNA damage.
abstract: Tip60 is a multifunctional acetyltransferase involved in multiple cellular functions. Acetylation of p53 at K120 by Tip60 promotes p53-mediated apoptosis after DNA damage. We previous showed that Tip60 activity is induced by phosphorylation at T158 by p38. In this study, we investigated the role of p38-mediated Tip60 phosphorylation in p53-mediated, DNA damage-induced apoptosis. We found that DNA damage induces p38 activation, Tip60-T158 phosphorylation, and p53-K120 acetylation with similar kinetics. p38α is essential for DNA damage-induced Tip60-T158 phosphorylation. In addition, both p38α and Tip60 are essential for p53-K120 acetylation, binding of p53 to PUMA promoter, PUMA expression and apoptosis induced by DNA damage. Moreover, DNA damage induces protein kinase activity of p38α towards Tip60-T158, and constitutive activation of p38 in cells leads to increases in Tip60-T158 phosphorylation, p53-K120 acetylation, PUMA expression and apoptosis. Furthermore, the Tip60-T158A mutant that cannot be phosphorylated by p38 fails to mediate p53-K120 acetylation, PUMA induction, and apoptosis following DNA damage. These results establish that Tip60-T158 phosphorylation by p38 plays an essential role in stimulating Tip60 activity required for inducing the p53-PUMA pathway that ultimately leads to apoptosis in response to DNA damage, which provides a mechanistic basis for the tumor-suppressing function of p38 and Tip60.
authors.affiliation: College of Medicine, Nankai University, Tianjin, P.R. China, 300071. Departments of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Yingxi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Departments of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Rong
authors.initials: R
authors.lastname: Liao
authors.affiliation: College of Medicine, Nankai University, Tianjin, P.R. China, 300071.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: College of Medicine, Nankai University, Tianjin, P.R. China, 300071.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Departments of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Sun
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D048308:Mitogen-Activated Protein Kinase 14