Downregulation of integrins by von Hippel-Lindau (VHL) tumor suppressor protein is independent of VHL-directed hypoxia-inducible factor alpha degradation.
Downregulation of integrins by von Hippel-Lindau (VHL) tumor suppressor protein is independent of VHL-directed hypoxia-inducible factor alpha degradation.
复制标题
von Hippel-Lindau (VHL) 肿瘤抑制蛋白对整合素的下调与 VHL 引导的缺氧诱导因子 α 降解无关。
DOI：
10.1139/o08-035
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Burk,RobertD
中科院分区：
文献类型：
--
作者：
Ji,Qingzhou;Burk,RobertD
大多数透明细胞肾细胞癌 (RCC) 中都会出现 von Hippel-Lindau (VHL) 肿瘤抑制基因失活。之前的研究表明，VHL 降低了整合素 α2、α5 和 β1 的丰度，这与 VHL 相关的细胞-细胞和细胞-细胞外基质粘附的变化一致。我们研究了 VHL 下调整合素的机制。尽管 VHL 可以靶向缺氧诱导因子 α (HIFα) 亚基进行降解，但 VHL 依赖性整合素的减少与 O2 浓度和 HIFα 水平无关。 VHL 缩短了整合素的半衰期，并且这种活性被蛋白酶体抑制所阻断。尽管异位表达的 FLAG-VHL 保留了 HIFα 降解活性，但与表达的野生型 VHL 相比，它既不下调整合素，也不促进粘附和细胞间紧密连接。此外，整合素与野生型 VHL 共免疫沉淀，但与 FLAG-VHL 不共沉淀。这些数据表明，VHL 对整合素的下调与 VHL 对 HIFα 亚基的调节不同，并且表明这种活性的丧失通过破坏粘附和紧密连接而导致 VHL 相关的 RCC 发展。
Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene occurs in the majority of clear-cell renal cell carcinomas (RCCs). It was previously shown that VHL decreased the abundance of integrins α2, α5, and β1, which is consistent with VHL-associated changes in cell–cell and cell – extracellular matrix adhesions. We investigated the mechanism by which VHL downregulates integrins. Although VHL can target hypoxia-inducible factor alpha (HIFα) subunits for degradation, VHL-dependent reduction of integrins was independent of O2concentration and HIFα levels. VHL reduced the half-lives of integrins, and this activity was blocked by proteasomal inhibition. Although ectopically expressed FLAG-VHL retained HIFα degradation activity, it neither downregulated integrins nor promoted adherens and tight intercellular junctions, in contrast to expressed wild-type VHL. Moreover, integrins co-immunoprecipitated with wild-type VHL, but not FLAG-VHL. These data indicate that the downregulation of integrins by VHL is distinct from the regulation of HIFα subunits by VHL, and suggests that the loss of this activity contributes to VHL-associated RCC development through disruption of adherens and tight junctions.