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The anaphase-promoting complex/cyclosome is an E3 ubiquitin ligase for Mdm2.

ABSTRACT: The Mdm2 proto-oncoprotein is the primary negative regulator for p53. While it is believed that Mdm2 degradation is regulated via its own E3 ubiquitin ligase activity, recent development of knock-in mouse models demonstrates that Mdm2 E3 ligase function is dispensable for self-degradation in vivo. Here, we show that the anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase for Mdm2 degradation. We demonstrate that APC2, a scaffold subunit of APC/C, binds to Mdm2 and is required for Mdm2 polyubiquitination and proteasomal degradation. Downregulation of APC2 by RNAi results in transcription-independent accumulation of Mdm2 and attenuation of stress-induced p53 stabilization, leading to decreased senescence and increased cell survival. Furthermore, APC2 expression is frequently downregulated in human cancers; in tumor cell lines, APC2 downregulation correlates with Mdm2 overexpression. Our study shows the regulation of Mdm2 by the E3 ubiquitin ligase APC/C and has important therapeutic implications for tumors with Mdm2 overexpression.

SUBMITTER: He Y

PROVIDER: S-EPMC4111701 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The anaphase-promoting complex/cyclosome is an E3 ubiquitin ligase for Mdm2.

He Yizhou Y Tollini Laura L Kim Tae-Hyung TH Itahana Yoko Y Zhang Yanping Y

Cell cycle (Georgetown, Tex.) 20140507 13

The Mdm2 proto-oncoprotein is the primary negative regulator for p53. While it is believed that Mdm2 degradation is regulated via its own E3 ubiquitin ligase activity, recent development of knock-in mouse models demonstrates that Mdm2 E3 ligase function is dispensable for self-degradation in vivo. Here, we show that the anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase for Mdm2 degradation. We demonstrate that APC2, a scaffold subunit of APC/C, binds to Mdm2 and is required ...[more]

PMID: 24804778

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Project description:The regulation of fundamental aspects of neurobiological function has been linked to the ubiquitin signaling system (USS), which regulates the degradation and activity of proteins and is catalyzed by E1, E2, and E3 enzymes. The Anaphase-Promoting Complex (APC) is a multi-subunit E3 ubiquitin ligase that controls diverse developmental and signaling processes in post-mitotic neurons; however, potential roles for the APC in sensory function have yet to be explored. In this study, we examined the effect of the APC ubiquitin ligase on chemosensation in Caenorhabditis elegans by testing chemotaxis to the volatile odorants, diacetyl, pyrazine, and isoamyl alcohol, to which wild-type worms are attracted. Animals with loss of function mutations in either of two alleles (g48 and ye143) of the gene encoding the APC subunit EMB-27 APC6 showed increased chemotaxis towards diacetyl and pyrazine, odorants sensed by AWA neurons, but exhibited normal chemotaxis to isoamyl alcohol, which is sensed by AWC neurons. The statistically significant increase in chemotaxis in the emb-27 APC6 mutants suggests that the APC inhibits AWA-mediated chemosensation in C. elegans. Increased chemotaxis to pyrazine was also seen with mutants lacking another essential APC subunit, MAT-2 APC1; however, mat-2 APC1 mutants exhibited wild type responses to diacetyl. The difference in responsiveness of these two APC subunit mutants may be due to differential strength of these hypomorphic alleles or may indicate the presence of functional sub-complexes of the APC at work in this process. These findings are the first evidence for APC-mediated regulation of chemosensation and lay the groundwork for further studies aimed at identifying the expression levels, function, and targets of the APC in specific sensory neurons. Because of the similarity between human and C. elegans nervous systems, the role of the APC in sensory neurons may also advance our understanding of human sensory function and disease.

Dataset Information

The anaphase-promoting complex/cyclosome is an E3 ubiquitin ligase for Mdm2.

Publications

The anaphase-promoting complex/cyclosome is an E3 ubiquitin ligase for Mdm2.

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