VHL 通过 HIF-2α 通路和泛素蛋白酶体通路调节肾癌细胞中的 NEK1。
VHL regulates NEK1 via both HIF-2α pathway and ubiquitin-proteasome pathway in renal cancer cell.
机构信息
Department of Pharmacology, School of Medicine, Taizhou University, China; Institute of Tumor, Taizhou University, China.
Institute of Tumor, Taizhou University, China.
出版信息
Biochem Biophys Res Commun. 2019 Feb 12;509(3):797-802. doi: 10.1016/j.bbrc.2019.01.001. Epub 2019 Jan 8.
Both Von Hippel-Lindau tumor suppressor (VHL) and Never-in-mitosis A (NIMA)-related kinase 1 (NEK1) are involved in primary cilium formation, but whether VHL could regulate NEK1 is unknown. Here, we demonstrated that renal cancer cells Caki-1 and ACHN with wild-type VHL expressed lower level of NEK1 than that of VHL-defective cells including 786-O, 769-P and A498 cells. VHL-overexpression down-regulated NEK1 in 769-P cells, while VHL-knockdown up-regulated NEK1 in Caki-1 cells. In addition, we found the hypoxia response element (HRE) in the promoter sequence of NEK1 and hypoxia induced NEK1 expression both in vitro and in vivo. HIF-2α knockdown blocked hypoxia induced NEK1 upregulation instead of HIF-1α, which indicates that NEK1 may be a new target of HIF-2α. Moreover, we confirmed the association between VHL and NEK1 in Caki-1 cell, then showed VHL promoted NEK1 protein degradation and ubiquitination. In conclusion, our findings showed VHL regulates NEK1 via both HIF-2α pathway and ubiquitin-proteasome pathway in renal cancer cells.
希佩尔-林道肿瘤抑制因子（VHL）和无丝分裂 A 相关激酶 1（NEK1）都参与了初级纤毛的形成，但 VHL 是否能调节 NEK1 尚不清楚。在这里，我们证明了具有野生型 VHL 的肾癌细胞 Caki-1 和 ACHN 的 NEK1 表达水平低于包括 786-O、769-P 和 A498 细胞在内的 VHL 缺陷型细胞。VHL 过表达可下调 769-P 细胞中的 NEK1，而 VHL 敲低可上调 Caki-1 细胞中的 NEK1。此外，我们发现了 NEK1 启动子序列中的缺氧反应元件（HRE），并在体外和体内均发现了缺氧诱导的 NEK1 表达。HIF-2α 敲低阻断了缺氧诱导的 NEK1 上调，而不是 HIF-1α，这表明 NEK1 可能是 HIF-2α 的一个新靶点。此外，我们在 Caki-1 细胞中证实了 VHL 和 NEK1 之间的关联，然后表明 VHL 促进了 NEK1 蛋白的降解和泛素化。总之，我们的研究结果表明，VHL 通过缺氧诱导因子-2α通路和泛素-蛋白酶体通路在肾癌细胞中调节 NEK1。
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