title: Otub1 stabilizes MDMX and promotes its proapoptotic function at the mitochondria.
abstract: Otub1 regulates p53 stability and activity via non-canonical inhibition of UbcH5, the MDM2 cognate ubiquitin-conjugating enzyme (E2). However, whether Otub1 regulates MDMX stability and activity is not clear. Here we report that Otub1 also suppresses MDM2-mediated MDMX ubiquitination in cells and in vitro, independently of its deubiquitinating enzyme activity. Consequently, overexpression of Otub1 markedly stabilized MDMX and increased its levels, whereas knockdown of Otub1 reduced the levels of MDMX. Interestingly, MDMX induced by Otub1 can localize to mitochondria in addition to the cytosol, enhance p53 phosphorylation at S46 (p53S46P) and promote mitochondria-mediated apoptotic pathway. Knockdown of MDMX reduced Otub1-induced p53S46P, which was shown to be critical for p53's mitochondrial function and apoptotic activity. Furthermore, Otub1 promotes UV-irradiation-induced p53S46P and apoptosis, which can be significantly inhibited by MDMX depletion. Together, these results suggest that Otub1 stabilizes MDMX and promotes p53S46P and mitochondria-mediated apoptosis, providing an alternative mechanism of Otub1's role in apoptosis.
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine, and The OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Yingxiao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine, and The OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Yue-Gang
authors.initials: YG
authors.lastname: Wang
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine, and The OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Yuhuang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine, and The OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Xiao-Xin
authors.initials: XX
authors.lastname: Sun
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine, and The OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Mu-Shui
authors.initials: MS
authors.lastname: Dai
mesh_terms: D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D000072017:Deubiquitinating Enzymes; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D014466:Ultraviolet Rays
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D012694:Serine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D000072017:Deubiquitinating Enzymes; C538826:OTUB1 protein, human; D003546:Cysteine Endopeptidases
keywords: MDMX; Otub1; apoptosis; deubiquitinating enzymes; p53