HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability
HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability
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DOI：
10.1016/j.ccr.2005.06.017
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发表时间：
2005-08-01
期刊：
影响因子：
50.3
通讯作者：
Neckers, L
中科院分区：
文献类型：
--
作者：
Isaacs, JS;Jung, YJ;Neckers, L
具有半合子胚系富马酸水合酶(FH)突变的个体容易患肾癌。这些肿瘤主要表现为剩余的野生型等位基因的功能失活，暗示FH失活是肿瘤促进事件。低氧诱导因子在许多癌症中表达，并在透明细胞肾癌中增加。在常氧条件下，由于依赖VHL的蛋白酶体降解，HIF是不稳定的，但在低氧条件下，由于HIF Pro羟基酶(HPH)的失活，使HIF稳定，从而阻止HIF羟化和VHL识别。我们证明，FH抑制和细胞内富马酸升高与HIF上调是一致的。此外，我们还发现富马酸对HPH具有竞争性抑制作用。这些数据描绘了一种新的富马酸依赖的调节HPH活性和HIF蛋白水平的途径。
Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.