The Roles of VHL-Dependent Ubiquitination in Signaling and Cancer.
The Roles of VHL-Dependent Ubiquitination in Signaling and Cancer.
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DOI：
10.3389/fonc.2012.00035
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发表时间：
2012
影响因子：
4.7
通讯作者：
Yang H
中科院分区：
文献类型：
--
作者：
Zhang Q;Yang H
在绝大多数肾透明细胞癌中，肿瘤抑制因子VHL的功能受损，其突变或表达缺失是导致这种疾病的原因。pVHL被发现是E3泛素连接酶的底物识别亚基，并且大多数肿瘤衍生的突变破坏了该功能。pVHL被发现与缺氧诱导因子（HIF）的α亚基结合并促进其泛素化和蛋白酶体降解。HIFα关键位点上的脯氨酸羟基化为pVHL E3连接酶复合物提供结合信号。除HIFα外，还发现了其他几种VHL靶点，包括活化的表皮生长因子受体（EGFR）、RNA聚合酶II亚基RPB 1和hsRPB 7、非典型蛋白激酶C（PKC）、Sprouty 2、β-肾上腺素能受体II和Myb结合蛋白p160。HIFα是研究最充分的底物，已被证明对pVHL的肿瘤抑制功能至关重要，但活化的EGFR和PKC以及其他pVHL底物也可能对肿瘤生长和药物反应很重要。他们的条例pVHL和他们的相关性信号和癌症进行了讨论。
The function of tumor suppressor VHL is compromised in the vast majority of clear cell renal cell carcinoma, and its mutations or loss of expression was causal for this disease. pVHL was found to be a substrate recognition subunit of an E3 ubiquitin ligase, and most of the tumor-derived mutations disrupt this function. pVHL was found to bind to the alpha subunits of hypoxia-inducible factor (HIF) and promote their ubiquitination and proteasomal degradation. Proline hydroxylation on key sites of HIFα provides the binding signal for pVHL E3 ligase complex. Beside HIFα, several other VHL targets have been identified, including activated epidermal growth factor receptor (EGFR), RNA polymerase II subunits RPB1 and hsRPB7, atypical protein kinase C (PKC), Sprouty2, β-adrenergic receptor II, and Myb-binding protein p160. HIFα is the most well studied substrate and has been proven to be critical for pVHL’s tumor suppressor function, but the activated EGFR and PKC and other pVHL substrates might also be important for tumor growth and drug response. Their regulations by pVHL and their relevance to signaling and cancer are discussed.