title: XAF1 directs apoptotic switch of p53 signaling through activation of HIPK2 and ZNF313.
abstract: X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a tumor suppressor that is frequently inactivated in many human cancers. However, the molecular mechanism underlying its growth-inhibitory function remains largely unknown. Here, we report that XAF1 forms a positive feedback loop with p53 and acts as a molecular switch in p53-mediated cell-fate decisions favoring apoptosis over cell-cycle arrest. XAF1 binds directly to the N-terminal proline-rich domain of p53 and thus interferes with E3 ubiquitin ligase MDM2 binding and ubiquitination of p53. XAF1 stimulates homeodomain-interacting protein kinase 2 (HIPK2)-mediated Ser-46 phosphorylation of p53 by blocking E3 ubiquitin ligase Siah2 interaction with and ubiquitination of HIPK2. XAF1 also steps up the termination of p53-mediated cell-cycle arrest by activating zinc finger protein 313 (ZNF313), a p21(WAF1)-targeting ubiquitin E3 ligase. XAF1 interacts with p53, Siah2, and ZNF313 through the zinc finger domains 5, 6, and 7, respectively, and truncated XAF1 isoforms preferentially expressed in cancer cells fail to form a feedback loop with p53. Together, this study uncovers a novel role for XAF1 in p53 stress response, adding a new layer of complexity to the mechanisms by which p53 determines cell-fate decisions.
authors.affiliation: Department of Life Sciences, Korea University, Seoul 136-701, Korea.
authors.forename: Min-Goo
authors.initials: MG
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Korea University, Seoul 136-701, Korea.
authors.forename: Jikhyon
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Life Sciences, Korea University, Seoul 136-701, Korea.
authors.forename: Seong-In
authors.initials: SI
authors.lastname: Jeong
authors.affiliation: Department of Life Sciences, Korea University, Seoul 136-701, Korea.
authors.forename: Nam-Gu
authors.initials: NG
authors.lastname: Her
authors.affiliation: Department of Life Sciences, Korea University, Seoul 136-701, Korea.
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Korea University, Seoul 136-701, Korea.
authors.forename: Tae-Kyu
authors.initials: TK
authors.lastname: Ha
authors.affiliation: Department of Life Sciences, Korea University, Seoul 136-701, Korea.
authors.forename: Min-Ju
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: Department of Life Sciences, Korea University, Seoul 136-701, Korea.
authors.forename: Byung-Kyu
authors.initials: BK
authors.lastname: Ryu
authors.affiliation: Department of Life Sciences, Korea University, Seoul 136-701, Korea chi6302@korea.ac.kr.
authors.forename: Sung-Gil
authors.initials: SG
authors.lastname: Chi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D025461:Feedback, Physiological / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012074:Remission Induction; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D000098563:Seven in Absentia Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; C417551:XAF1 protein, human; D010768:Phosphoserine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C477146:RNF114 protein, human; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: HIPK2; Siah2; XAF1; ZNF313; p53