title: Phosphorylation of von Hippel-Lindau protein by checkpoint kinase 2 regulates p53 transactivation.
abstract: von-Hippel Lindau protein (pVHL) suppresses tumorigenesis in the kidney, in part through regulation of hypoxia-inducible factor alpha (HIF alpha). However, HIF has been proposed to be necessary but insufficient for renal tumorigenesis. p53 was implicated as a transcription factor that is regulated by pVHL, but the molecular mechanism by which pVHL regulates p53 on DNA damage is unknown. We demonstrated that checkpoint kinase-2 (Chk2) binds to the beta-domain of pVHL and phosphorylates Ser 111 on DNA damage. Notably, this modification enhances pVHL-mediated transactivation of p53 by recruiting p300 and Tip60 to the chromatin of p53 target gene. Further, the naturally occurring pVHL mutants pVHL-S111R and pVHL-S111C showed diminished binding to coactivators, ultimately retarding p53-mediated growth arrest and apoptosis. In this study, we determined the molecular mechanism by which pVHL transactivates p53 on DNA damage and demonstrated that p53-related pVHL subtype mutants regulate tumorigenecity in VHL diseases.
authors.affiliation: National Research Laboratory for Metabolic Checkpoint, Departments of Biomedical Sciences and Biochemistry and Molecular Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae-Seok
authors.initials: JS
authors.lastname: Roe
authors.forename: Hwa-Ryeon
authors.initials: HR
authors.lastname: Kim
authors.forename: In-Young
authors.initials: IY
authors.lastname: Hwang
authors.forename: Nam-Chul
authors.initials: NC
authors.lastname: Ha
authors.forename: Seong-Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Cho
authors.forename: Hong-Duk
authors.initials: HD
authors.lastname: Youn
mesh_terms: D017209:Apoptosis / Q000235:genetics; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D045325:HCT116 Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D012694:Serine; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases