title: Heat shock protein gp96 decreases p53 stability by regulating Mdm2 E3 ligase activity in liver cancer.
abstract: The resistance to apoptosis displayed by liver cancer plays a key role in hepatocarcinogenesis, tumor progression, and resistance to chemo- or radio-therapy. In this study, we uncovered the potential role and mechanism of heat shock protein gp96 in regulating liver tumor cell growth and apoptosis. P53 protein was identified as a gp96 client protein by profiling apoptosis-related proteins in gp96-knockdown liver cancer cells. Overexpression and knockdown studies both demonstrated that gp96 decreases p53 protein levels, and gp96 regulated cell apoptosis in a p53-dependent manner. We further provide evidence that gp96 interacts with both p53 and Mdm2 to enhance Mdm2-mediated p53 ubiquitination and degradation. Moreover, targeting gp96 with siRNA induced cell apoptosis and led to the suppression of liver tumor growth in vivo. In conclusion, we elucidated an underlying mechanism by which gp96 promotes p53 degradation via increasing Mdm2 E3 ligase activity and provided a new therapeutic strategy to target the gp96-mediated anti-apoptotic characteristic of hepatocellular carcinoma.
authors: School of Life Sciences, Anhui University, Hefei, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
authors: Bo
authors: B
authors: Wu
authors: School of Life Sciences, Anhui University, Hefei, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
authors: Xiaoyu
authors: X
authors: Chu
authors: School of Life Sciences, Anhui University, Hefei, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
authors: Cong
authors: C
authors: Feng
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
authors: Junwei
authors: J
authors: Hou
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
authors: Hongxia
authors: H
authors: Fan
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
authors: Ningning
authors: N
authors: Liu
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
authors: Changfei
authors: C
authors: Li
authors: Transgenic Engineering Research Laboratory, Infectious Disease Center, 458th Hospital, Guangzhou, China.
authors: Xianping
authors: X
authors: Kong
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
authors: Xin
authors: X
authors: Ye
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Electronic address: mengsd@im.ac.cn.
authors: Songdong
authors: S
authors: Meng
mesh_terms: D000818:Animals; D017209:Apoptosis; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D008562:Membrane Glycoproteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C053387:endoplasmin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Apoptosis; Chaperone; Ubiquitination; gp96