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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ankyrins / metabolism
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Apoptosis
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Cells, Cultured
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Gene Expression Regulation*
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Humans
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Immunoprecipitation
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Mice
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Molecular Sequence Data
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Neoplasms / metabolism
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Neoplasms / pathology
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Nuclear Proteins / metabolism*
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Proteasome Endopeptidase Complex / metabolism*
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Proteasome Inhibitors
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-mdm2
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RNA, Small Interfering / pharmacology
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Zinc Fingers
Substances
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Ankyrins
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Nuclear Proteins
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PSMD10 protein, human
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Proteasome Inhibitors
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Retinoblastoma Protein
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2
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Proteasome Endopeptidase Complex
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ATP dependent 26S protease
Associated data
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GENBANK/D83197
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GENBANK/K03199
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GENBANK/Z12021