The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies.
The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies.
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DOI：
10.5732/cjc.012.10279
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发表时间：
2013-09
影响因子：
--
通讯作者：
Zhou PB
中科院分区：
文献类型：
--
作者：
Hannah J;Zhou PB
Cullin 4A（CUL4A）是一种E3泛素连接酶，通过靶向包括损伤特异性DNA结合蛋白2（DDB2）、着色性干皮病互补组C（XPC）、染色质许可和DNA复制因子1（Cdt1）和p21在内的底物，直接影响DNA修复和细胞周期进程。我们实验室最近的工作表明，Cul4a缺陷小鼠大大降低了紫外线诱导的皮肤癌的发病率。在细胞水平上，Cul4a缺陷细胞具有很大的DNA修复能力，并表现出缓慢的增殖速率，主要是由于DDB2和p21的表达分别增加。这表明CUL4A通过限制DNA修复活性和加速S期进入促进肿瘤发生（以及皮肤损伤的积累和随后的过早衰老）。此外，已经发现CUL4A在乳腺癌、肝细胞癌、鳞状细胞癌、肾上腺皮质癌、儿童髓母细胞瘤和恶性胸膜间皮瘤中通过基因扩增或过表达而上调。由于其在皮肤癌中的致癌活性和在其他恶性肿瘤中的上调，CUL4A已成为靶向治疗方法的潜在候选者。在这篇综述中，我们概述了CUL4A的既定功能，并讨论了E3连接酶作为肿瘤发生的潜在驱动因素的出现。
Cullin 4A (CUL4A) is an E3 ubiquitin ligase that directly affects DNA repair and cell cycle progression by targeting substrates including damage-specific DNA-binding protein 2 (DDB2), xeroderma pigmentosum complementation group C (XPC), chromatin licensing and DNA replication factor 1 (Cdt1), and p21. Recent work from our laboratory has shown that Cul4a-deficient mice have greatly reduced rates of ultraviolet-induced skin carcinomas. On a cellular level, Cul4a-deficient cells have great capacity for DNA repair and demonstrate a slow rate of proliferation due primarily to increased expression of DDB2 and p21, respectively. This suggests that CUL4A promotes tumorigenesis (as well as accumulation of skin damage and subsequent premature aging) by limiting DNA repair activity and expediting S phase entry. In addition, CUL4A has been found to be up-regulated via gene amplification or overexpression in breast cancers, hepatocellular carcinomas, squamous cell carcinomas, adrenocortical carcinomas, childhood medulloblastomas, and malignant pleural mesotheliomas. Because of its oncogenic activity in skin cancer and up-regulation in other malignancies, CUL4A has arisen as a potential candidate for targeted therapeutic approaches. In this review, we outline the established functions of CUL4A and discuss the E3 ligase's emergence as a potential driver of tumorigenesis.
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