title: The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1.
abstract: Proapoptotic Bcl-2 family members, such as Bax, promote release of cytochrome c from mitochondria, leading to caspase activation and cell death. It was previously reported that modulator of apoptosis protein 1 (MOAP-1), an enhancer of Bax activation induced by DNA damage, is stabilized by Trim39, a protein of unknown function. In this paper, we show that MOAP-1 is a novel substrate of the anaphase-promoting complex (APC/C(Cdh1)) ubiquitin ligase. The influence of Trim39 on MOAP-1 levels stems from the ability of Trim39 (a RING domain E3 ligase) to directly inhibit APC/C(Cdh1)-mediated protein ubiquitylation. Accordingly, small interfering ribonucleic acid-mediated knockdown of Cdh1 stabilized MOAP-1, thereby enhancing etoposide-induced Bax activation and apoptosis. These data identify Trim39 as a novel APC/C regulator and provide an unexpected link between the APC/C and apoptotic regulation via MOAP-1.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Nai-Jia
authors.initials: NJ
authors.lastname: Huang
authors.forename: Liguo
authors.initials: L
authors.lastname: Zhang
authors.forename: Wanli
authors.initials: W
authors.lastname: Tang
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Chih-Sheng
authors.initials: CS
authors.lastname: Yang
authors.forename: Sally
authors.initials: S
authors.lastname: Kornbluth
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D015703:Antigens, CD; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005434:Flow Cytometry; D016193:G1 Phase / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C555337:APC protein, human; D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C513384:CDH1 protein, human; D015820:Cadherins; D002352:Carrier Proteins; C428449:MOAP1 protein, human; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D025801:Ubiquitin; D051028:bcl-2-Associated X Protein; C414583:TRIM39 protein, human; D044767:Ubiquitin-Protein Ligases