title: The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53.
abstract: Gankyrin is an ankyrin repeat oncoprotein commonly overexpressed in hepatocellular carcinomas. Gankyrin interacts with the S6 proteasomal ATPase and accelerates the degradation of the tumor suppressor Rb. We show here that gankyrin has an antiapoptotic activity in cells exposed to DNA damaging agents. Downregulation of gankyrin induces apoptosis in cells with wild-type p53. In vitro and in vivo experiments revealed that gankyrin binds to Mdm2, facilitating p53-Mdm2 binding, and increases ubiquitylation and degradation of p53. Gankyrin also enhances Mdm2 autoubiquitylation in the absence of p53. Downregulation of gankyrin reduced amounts of Mdm2 and p53 associated with the 26S proteasome. Thus, gankyrin is a cofactor that increases the activities of Mdm2 on p53 and probably targets polyubiquitylated p53 into the 26S proteasome.
authors: Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Hiroaki
authors: H
authors: Higashitsuji
authors: Hisako
authors: H
authors: Higashitsuji
authors: Katsuhiko
authors: K
authors: Itoh
authors: Toshiharu
authors: T
authors: Sakurai
authors: Toshikazu
authors: T
authors: Nagao
authors: Yasuhiko
authors: Y
authors: Sumitomo
authors: Haruhiko
authors: H
authors: Sumitomo
authors: Tomoko
authors: T
authors: Masuda
authors: Simon
authors: S
authors: Dawson
authors: Yutaka
authors: Y
authors: Shimada
authors: R John
authors: RJ
authors: Mayer
authors: Jun
authors: J
authors: Fujita
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D017209:Apoptosis; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D034741:RNA, Small Interfering / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: D017487:Ankyrins; D009687:Nuclear Proteins; C403591:PSMD10 protein, human; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease