Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein
Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein
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DOI：
10.1016/s1535-6108(02)00043-0
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发表时间：
2002-04-01
期刊：
影响因子：
50.3
通讯作者：
Kaelin, WG
中科院分区：
文献类型：
--
作者：
Kondo, K;Klco, J;Kaelin, WG
Von Hippel-Lindau肿瘤抑制基因的失活与遗传性(VHL疾病相关)和散发性肾透明细胞癌的发生有关。VHL基因产物pVHL针对异二聚体转录因子HIF进行多泛素化，VHL-/-肾癌细胞中pVHL功能的恢复抑制了它们在裸鼠体内形成肿瘤的能力。在这里，我们展示了pVHL对肿瘤的抑制可以被逃脱pVHL控制的HIF变体所覆盖。这些研究证明，HIF是pVHL的关键下游靶基因，并证实HIF靶基因的激活可以促进体内肿瘤的发生。
Inactivation of the von Hippel-Lindau tumor suppressor gene is linked to the development of hereditary (VHL Disease-associated) and sporadic clear cell carcinoma of the kidney. The VHL gene product, pVHL, targets the heterodimeric transcription factor HIF for polyubiquitination, and restoration of pVHL function in VHL-/- renal carcinoma cells suppresses their ability to form tumors in nude mice. Here we show that tumor suppression by pVHL can be overridden by a HIF variant that escapes pVHL control. These studies prove that HIF is a critical downstream target of pVHL and establish that activation of HIF target genes can promote tumorigenesis in vivo.