Functional characterization of Anaphase Promoting Complex/Cyclosome (APC/C) E3 ubiquitin ligases in tumorigenesis

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• 作者：Jinfang Zhang^a ; ¹ ; Lixin Wan^a ; ¹ ; Xiangpeng Dai^a ; Yi Sun^b ; Wenyi Wei^a ; ^{wwei2@bidmc.harvard.edu" class="auth_mail}
• 关键词：APC/C ; Anaphase Promoting Complex/Cyclosome ; AOM ; azoxymethane ; Bub3 ; budding uninhibited by benzimidazole protein 3 ; BubR1 ; bub1-related protein ; Cdc20 ; cell division cycle 20 ; Cdh1 ; Cdc20 homologue protein 1 ; DMBA ; 7 ; 12-dimethylbenz-伪-anthracene ; Emi1 ; early mitotic inhibitor 1 ; FBW7 ; F-box and WD-40 repeat domain containing protein 7 ; H ; hypomorphic allele ; HECT ; homologous to the E6-AP carboxyl terminus ; KO ; knockout ; L-LTP ; late-phase long-term potentiation ; Mad2 ; mitotic arrest deficient
• 刊名：Biochimica et Biophysica Acta (BBA)/Reviews on Cancer
• 出版年：April, 2014
• 年：2014
• 卷：1845
• 期：2
• 页码：277-293
• 全文大小：1045 K

文摘

The Anaphase Promoting Complex/Cyclosome (APC/C) is a multi-subunit E3 ubiquitin ligase that primarily governs cell cycle progression. APC/C is composed of at least 14 core subunits and recruits its substrates for ubiquitination via one of the two adaptor proteins, Cdc20 or Cdh1, in M or M/early G1 phase, respectively. Furthermore, recent studies have shed light on crucial functions for APC/C in maintaining genomic integrity, neuronal differentiation, cellular metabolism and tumorigenesis. To gain better insight into the in vivo physiological functions of APC/C in regulating various cellular processes, particularly development and tumorigenesis, a number of mouse models of APC/C core subunits, coactivators or inhibitors have been established and characterized. However, due to their essential role in cell cycle regulation, most of the germline knockout mice targeting the APC/C pathway are embryonic lethal, indicating the need for generating conditional knockout mouse models to assess the role in tumorigenesis for each APC/C signaling component in specific tissues. In this review, we will first provide a brief introduction of the ubiquitin-proteasome system (UPS) and the biochemical activities and cellular functions of the APC/C E3 ligase. We will then focus primarily on characterizing genetic mouse models used to understand the physiological roles of each APC/C signaling component in embryogenesis, cell proliferation, development and carcinogenesis. Finally, we discuss future research directions to further elucidate the physiological contributions of APC/C components during tumorigenesis and validate their potentials as a novel class of anti-cancer targets.