Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and key regulator of cell cycle progression. Since APC/C promotes the degradation of mitotic cyclins, it controls cell cycle-dependent oscillations in cyclin-dependent kinase (CDK) activity. Both CDKs and APC/C control a large number of substrates and are regulated by analogous mechanisms, including cofactor-dependent activation. However, whereas substrate dephosphorylation is known to counteract CDK, it remains largely unknown whether deubiquitinating enzymes (DUBs) antagonize APC/C substrate ubiquitination during mitosis. Here, we demonstrate that Cezanne/OTUD7B is a cell cycle-regulated DUB that opposes the ubiquitination of APC/C targets. Cezanne is remarkably specific for K11-linked ubiquitin chains, which are formed by APC/C in mitosis. Accordingly, Cezanne binds established APC/C substrates and reverses their APC/C-mediated ubiquitination. Cezanne depletion accelerates APC/C substrate degradation and causes errors in mitotic progression and formation of micronuclei. These data highlight the importance of tempered APC/C substrate destruction in maintaining chromosome stability. Furthermore, Cezanne is recurrently amplified and overexpressed in numerous malignancies, suggesting a potential role in genome maintenance and cancer cell proliferation.
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PMID:Cezanne/OTUD7B is a cell cycle-regulated deubiquitinase that antagonizes the degradation of APC/C substrates. 2997 62

The Anaphase-Promoting Complex/Cyclosome (APC/C) is an E3 ubiquitin ligase and a key regulator of cell cycle progression. By triggering the degradation of mitotic cyclins, APC/C controls cell cycle-dependent oscillations in cyclin-dependent kinase (CDK) activity. Thus, the dynamic activities of both APC/C and CDK sit at the core of the cell cycle oscillator. The APC/C controls a large number of substrates and is regulated through multiple mechanisms, including cofactor-dependent activation. These cofactors, Cdc20 and Cdh1, recognize substrates, while the specific E2 enzymes UBE2C/UbcH10 and UBE2S cooperate with APC/C to build K11-linked ubiquitin chains on substrates to target them for proteasomal degradation. However, whether deubiquitinating enzymes (DUBs) can antagonize APC/C substrate ubiquitination during mitosis has remained largely unknown. We recently demonstrated that Cezanne/OTUD7B is a cell cycle-regulated DUB that opposes the ubiquitination of APC/C substrates. Cezanne binds APC/C substrates, reverses their ubiquitination and protects them from degradation. Accordingly, Cezanne depletion accelerates APC/C substrate degradation, leading to errors in mitotic progression and formation of micronuclei. Moreover, Cezanne is significantly amplified and overexpressed in breast cancers. This suggests a potential role for APC/C antagonism in the pathogenesis of disease. APC/C contributes to chromosome segregation fidelity in mitosis raising the possibility that copy-number and expression changes in Cezanne observed in cancer contribute to the etiology of disease. Collectively, these observations identify a new player in cell cycle progression, define mechanisms of tempered APC/C substrate destruction and highlight the importance of this regulation in maintaining chromosome stability.
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PMID:Impressionist portraits of mitotic exit: APC/C, K11-linked ubiquitin chains and Cezanne. 3087 63