title: Phosphorylation of Tip60 by GSK-3 determines the induction of PUMA and apoptosis by p53.
abstract: Activation of p53 by DNA damage results in either cell-cycle arrest, allowing DNA repair and cell survival, or induction of apoptosis. As these opposite outcomes are both mediated by p53 stabilization, additional mechanisms to determine this decision must exist. Here, we show that glycogen synthase kinase-3 (GSK-3) is required for the p53-mediated induction of the proapoptotic BH3 only-protein PUMA, an essential mediator of p53-induced apoptosis. Inhibition of GSK-3 protected from cell death induced by DNA damage and promoted increased long-term cell survival. We demonstrate that GSK-3 phosphorylates serine 86 of the p53-acetyltransferase Tip60. A Tip60(S86A) mutant was less active to induce p53 K120 acetylation, histone 4 acetylation, and expression of PUMA. Our data suggest that GSK-3 mediated Tip60S86 phosphorylation provides a link between PI3K signaling and the choice for or against apoptosis induction by p53.
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, Stefan Meier Strasse 17, 79104 Freiburg, Germany.
authors.forename: Céline
authors.initials: C
authors.lastname: Charvet
authors.forename: Manuela
authors.initials: M
authors.lastname: Wissler
authors.forename: Prisca
authors.initials: P
authors.lastname: Brauns-Schubert
authors.forename: Shang-Jui
authors.initials: SJ
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
authors.forename: Florian C
authors.initials: FC
authors.lastname: Sigloch
authors.forename: Hestia
authors.initials: H
authors.lastname: Mellert
authors.forename: Martin
authors.initials: M
authors.lastname: Brandenburg
authors.forename: Silke E
authors.initials: SE
authors.lastname: Lindner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Breit
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Steven B
authors.initials: SB
authors.lastname: McMahon
authors.forename: Christoph
authors.initials: C
authors.lastname: Borner
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Ulrich
authors.initials: U
authors.lastname: Maurer
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D038362:Glycogen Synthase Kinase 3