title: Ubiquitination-dependent degradation of p73 by the mitochondrial E3 ubiquitin ligase Hades.
abstract: p73 is a member of the p53 family of transcription factors which plays an essential role in tumor suppression. p73 is associated with the sensitivity of cancer cells to chemotherapy and the prognosis of many cancers. In this study, we showed the ubiquitination-dependent degradation of p73 by the mitochondrial E3 ubiquitin ligase Hades. First, the binding between p73 and Hades was identified by co-immunoprecipitation experiments, and it was found that the Hades RING-finger domain mediates the interaction with p73. Immunofluorescence analysis showed that p73 moves to the mitochondria and colocalizes with Hades during etoposide-induced apoptosis. By performing in vivo and in vitro ubiquitination assays, we observed that the Hades RING-finger domain promotes ubiquitination of p73. Finally, it was shown that SiRNA-mediated depletion of Hades stabilizes p73. Taken together, our results showed that Hades mediates the ubiquitination-dependent degradation of mitochondrial p73 under apoptotic conditions. These findings suggest that Hades-mediated p73 ubiquitination is a novel regulatory mechanism for the exonuclear function of p73.
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Republic of Korea.
authors.forename: Bumki
authors.initials: B
authors.lastname: Min
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Republic of Korea.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Structural Biology & Nanopore Research Laboratory, KRIBB, Daejeon 305-806, Republic of Korea. Electronic address: swchi@kribb.re.kr.
authors.forename: Seung-Wook
authors.initials: SW
authors.lastname: Chi
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Republic of Korea. Electronic address: gsyi@kaist.ac.kr.
authors.forename: Gwan-Su
authors.initials: GS
authors.lastname: Yi
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001665:Binding Sites; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D005047:Etoposide; C529067:MUL1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Hades; Mitochondria; RING-finger domain; Ubiquitination; p73