title: Arsenic trioxide reactivates proteasome-dependent degradation of mutant p53 protein in cancer cells in part via enhanced expression of Pirh2 E3 ligase.
abstract: The p53 gene is mutated in more than 50% of human tumors. Mutant p53 exerts an oncogenic function and is often highly expressed in cancer cells due to evasion of proteasome-dependent degradation. Thus, reactivating proteasome-dependent degradation of mutant p53 protein is an attractive strategy for cancer management. Previously, we found that arsenic trioxide (ATO), a drug for acute promyelocytic leukemia, degrades mutant p53 protein through a proteasome pathway. However, it remains unclear what is the E3 ligase that targets mutant p53 for degradation. In current study, we sought to identify an E3 ligase necessary for ATO-mediated degradation of mutant p53. We found that ATO induces expression of Pirh2 E3 ligase at the transcriptional level. We also found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, ATO-induced degradation of mutant p53 protein. Furthermore, we found that Pirh2 E3 ligase physically interacts with and targets mutant p53 for polyubiquitination and subsequently proteasomal degradation. Interestingly, we found that ATO cooperates with HSP90 or HDAC inhibitor to promote mutant p53 degradation and growth suppression in tumor cells. Together, these data suggest that ATO promotes mutant p53 degradation in part via induction of the Pirh2-dependent proteasome pathway.
authors.affiliation: Comparative Oncology Laboratory, School of Medicine and Veterinary Medicine, University of California at Davis, Davis, California, United States of America.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yan
authors.affiliation: Comparative Oncology Laboratory, School of Medicine and Veterinary Medicine, University of California at Davis, Davis, California, United States of America.
authors.forename: Yong-Sam
authors.initials: YS
authors.lastname: Jung
authors.affiliation: Comparative Oncology Laboratory, School of Medicine and Veterinary Medicine, University of California at Davis, Davis, California, United States of America.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Comparative Oncology Laboratory, School of Medicine and Veterinary Medicine, University of California at Davis, Davis, California, United States of America.
authors.forename: Xinbin
authors.initials: X
authors.lastname: Chen
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D050505:Mutant Proteins; D010087:Oxides / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D001152:Arsenicals; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D050505:Mutant Proteins; D010087:Oxides; D016159:Tumor Suppressor Protein p53; C485369:RCHY1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D000077237:Arsenic Trioxide