Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
J Cell Biol. 2010 Jan 11;188(1):83-100. doi: 10.1083/jcb.200906147.
The anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase functions with the E2 ubiquitin-conjugating enzyme UbcH10 in the orderly progression through mitosis by marking key mitotic regulators for destruction by the 26-S proteasome. UbcH10 is overexpressed in many human cancer types and is associated with tumor progression. However, whether UbcH10 overexpression causes tumor formation is unknown. To address this central question and to define the molecular and cellular consequences of UbcH10 overexpression, we generated a series of transgenic mice in which UbcH10 was overexpressed in graded fashion. In this study, we show that UbcH10 overexpression leads to precocious degradation of cyclin B by the APC/C, supernumerary centrioles, lagging chromosomes, and aneuploidy. Importantly, we find that UbcH10 transgenic mice are prone to carcinogen-induced lung tumors and a broad spectrum of spontaneous tumors. Our results identify UbcH10 as a prominent protooncogene that causes whole chromosome instability and tumor formation over a wide gradient of overexpression levels.
后期促进复合物/环体 (APC/C) E3 泛素连接酶与 E2 泛素缀合酶 UbcH10 一起发挥作用，通过标记关键的有丝分裂调节剂使其被 26-S 蛋白酶体破坏，从而有序地推进有丝分裂。UbcH10 在许多人类癌症类型中过度表达，并与肿瘤进展相关。然而，UbcH10 的过度表达是否会导致肿瘤形成尚不清楚。为了解决这个核心问题，并阐明 UbcH10 过度表达的分子和细胞后果，我们生成了一系列转基因小鼠，其中 UbcH10 以分级的方式过表达。在这项研究中，我们表明 UbcH10 的过度表达导致 APC/C 过早降解细胞周期蛋白 B、额外的中心粒、滞后染色体和非整倍体。重要的是，我们发现 UbcH10 转基因小鼠容易发生致癌物诱导的肺癌和广泛的自发性肿瘤。我们的结果表明 UbcH10 是一个主要的原癌基因，它在广泛的过表达水平梯度上导致全染色体不稳定性和肿瘤形成。
