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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Adenomatous Polyposis Coli Protein / genetics
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Adenomatous Polyposis Coli Protein / metabolism*
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Antigens, CD
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Apoptosis
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Apoptosis Regulatory Proteins / chemistry
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Blotting, Western
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Cadherins / antagonists & inhibitors
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Cadherins / genetics
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Cadherins / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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DNA Damage
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Flow Cytometry
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G1 Phase / physiology
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HeLa Cells
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Humans
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Immunoprecipitation
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RNA, Small Interfering / genetics
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Ubiquitin / metabolism*
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Ubiquitin-Protein Ligases
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Ubiquitination
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bcl-2-Associated X Protein / metabolism*
Substances
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APC protein, human
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Adaptor Proteins, Signal Transducing
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Adenomatous Polyposis Coli Protein
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Antigens, CD
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Apoptosis Regulatory Proteins
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BAX protein, human
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CDH1 protein, human
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Cadherins
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Carrier Proteins
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MOAP1 protein, human
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RNA, Small Interfering
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Recombinant Proteins
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Ubiquitin
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bcl-2-Associated X Protein
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TRIM39 protein, human
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Ubiquitin-Protein Ligases