Phosphorylation of Tip60 by p38α regulates p53-mediated PUMA induction and apoptosis in response to DNA damage. 2014

Yingxi Xu, and Rong Liao, and Na Li, and Rong Xiang, and Peiqing Sun
College of Medicine, Nankai University, Tianjin, P.R. China, 300071. Departments of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037.

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.

UI MeSH Term Description Entries
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D011518 Proto-Oncogene Proteins Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. Cellular Proto-Oncogene Proteins,c-onc Proteins,Proto Oncogene Proteins, Cellular,Proto-Oncogene Products, Cellular,Cellular Proto Oncogene Proteins,Cellular Proto-Oncogene Products,Proto Oncogene Products, Cellular,Proto Oncogene Proteins,Proto-Oncogene Proteins, Cellular,c onc Proteins
D004249 DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS. DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000074443 Lysine Acetyltransferase 5 A catalytic subunit of the NuA4 histone acetyltransferase complex that functions in transcriptional activation of genes by acetylation of nucleosomal HISTONES H4 and H2A, altering nucleosome-DNA interactions and interaction of the modified histones with other activating transcription factors. It may control gene expression changes associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest; CELL AGING; APOPTOSIS; and DNA REPAIR. It is polyubiquitinated and degraded during HIV-1 infection through its interaction with the viral TAT PROTEIN. HIV-1-Tat Interactive Protein Tip60,HTATIP,KAT5 (TIP60) Protein,HIV 1 Tat Interactive Protein Tip60
D016159 Tumor Suppressor Protein p53 Nuclear phosphoprotein encoded by the p53 gene (GENES, P53) whose normal function is to control CELL PROLIFERATION and APOPTOSIS. A mutant or absent p53 protein has been found in LEUKEMIA; OSTEOSARCOMA; LUNG CANCER; and COLORECTAL CANCER. p53 Tumor Suppressor Protein,Cellular Tumor Antigen p53,Oncoprotein p53,TP53 Protein,TRP53 Protein,p53 Antigen,pp53 Phosphoprotein,Phosphoprotein, pp53
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D048308 Mitogen-Activated Protein Kinase 14 A 38-kDa mitogen-activated protein kinase that is abundantly expressed in a broad variety of cell types. It is involved in the regulation of cellular stress responses as well as the control of proliferation and survival of many cell types. The kinase activity of the enzyme is inhibited by the pyridinyl-imidazole compound SB 203580. CSAID-Binding Protein,Cytokine Suppressive Anti-inflammatory Drug Binding Protein,Kinase CSBP,MAPK14,MAPK14 Mitogen-Activated Protein Kinase,MAX-Interacting Protein 2,Mxi2 Protein,SAPK2a,Stress-activated protein kinase 2a,p38alpha MAP Kinase,p38alpha Mitogen-Activated Protein Kinase,p38alphaMAPK,CSAID Binding Protein,CSBP, Kinase,Cytokine Suppressive Anti inflammatory Drug Binding Protein,MAP Kinase, p38alpha,MAPK14 Mitogen Activated Protein Kinase,MAX Interacting Protein 2,Mitogen Activated Protein Kinase 14,Stress activated protein kinase 2a,p38alpha Mitogen Activated Protein Kinase
D051017 Apoptosis Regulatory Proteins A large group of proteins that control APOPTOSIS. This family of proteins includes many ONCOGENE PROTEINS as well as a wide variety of classes of INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS such as CASPASES. Anti-Apoptotic Protein,Anti-Apoptotic Proteins,Apoptosis Inducing Protein,Apoptosis Inhibiting Protein,Apoptosis Regulatory Protein,Pro-Apoptotic Protein,Pro-Apoptotic Proteins,Programmed Cell Death Protein,Apoptosis Inducing Proteins,Apoptosis Inhibiting Proteins,Death Factors (Apoptosis),Programmed Cell Death Proteins,Survival Factors (Apoptosis),Anti Apoptotic Protein,Anti Apoptotic Proteins,Inducing Protein, Apoptosis,Inducing Proteins, Apoptosis,Inhibiting Protein, Apoptosis,Inhibiting Proteins, Apoptosis,Pro Apoptotic Protein,Pro Apoptotic Proteins,Protein, Anti-Apoptotic,Protein, Apoptosis Inducing,Protein, Apoptosis Inhibiting,Protein, Apoptosis Regulatory,Protein, Pro-Apoptotic,Proteins, Anti-Apoptotic,Proteins, Apoptosis Inducing,Proteins, Apoptosis Inhibiting,Proteins, Pro-Apoptotic,Regulatory Protein, Apoptosis,Regulatory Proteins, Apoptosis

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