Isaacs Jennifer S, Jung Yun Jin, Mole David R, Lee Sunmin, Torres-Cabala Carlos, Chung Yuen-Li, Merino Maria, Trepel Jane, Zbar Berton, Toro Jorge, Ratcliffe Peter J, Linehan W Marston, Neckers Len
Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
Cancer Cell. 2005 Aug;8(2):143-53. doi: 10.1016/j.ccr.2005.06.017.
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.
携带半合子生殖系富马酸水合酶（FH）突变的个体易患肾癌。这些肿瘤主要表现为剩余野生型等位基因的功能失活，这表明FH失活是一种促肿瘤事件。缺氧诱导因子在许多癌症中表达，在透明细胞肾细胞癌中表达增加。在常氧条件下，由于VHL依赖的蛋白酶体降解，HIFs不稳定，但在缺氧条件下，由于HIF脯氨酰羟化酶（HPH）失活，HIFs会发生稳定化，这会阻止HIF羟化和VHL识别。我们证明，FH抑制与细胞内富马酸升高同时发生时，会伴随HIF上调。此外，我们表明富马酸作为HPH的竞争性抑制剂。这些数据描绘了一条新的依赖富马酸的途径，用于调节HPH活性和HIF蛋白水平。
