VHL tumor suppressor regulates Cl-/HCO3- exchange and Na+/H+ exchange activities in renal carcinoma cells
VHL tumor suppressor regulates Cl-/HCO3- exchange and Na+/H+ exchange activities in renal carcinoma cells
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DOI：
10.1152/physiolgenomics.2001.5.3.119
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发表时间：
2001-04-02
影响因子：
4.6
通讯作者：
Sukhatme, VP
中科院分区：
文献类型：
--
作者：
Karumanchi, SA;Jiang, LW;Sukhatme, VP
von Hippel-Lindau（VHL）肿瘤抑制基因突变被认为在散发性和VHL疾病相关透明细胞肾癌（RCC）的发病机制中起关键作用。差异显示-PCR鉴定AE 2阴离子交换蛋白为候选VHL靶基因。AE 2 mRNA和多肽水平在786-O VHL细胞中比在786-O Neo细胞中高约3倍。相反，786-O VHL细胞中Cl-/HCO 3-交换活性比786-O Neo细胞低50%。由于静息细胞内pH（pH（i））值是无法区分的，我们推测，Na+/H+交换活性（NHE）可能类似地减少在786-O VHL细胞。NHE介导的pH（i）从酸负荷的恢复低于786-O Neo细胞的50%，而高渗刺激的阿米洛利敏感的NHE在两种细胞系中是不可区分的。786-O VHL中NHE 3 mRNA水平高于786-O Neo细胞，但NHE 1 mRNA水平无差异。AE 2和NHE 3是第一个被报道被pVHL上调的转录物。负责下调两个离子交换活动的机制的阐明将需要进一步的调查。
Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are thought to play a critical role in the pathogenesis of both sporadic and VHL disease-associated clear-cell renal carcinomas (RCC). Differential display-PCR identified the AE2 anion exchanger as a candidate VHL target gene. AE2 mRNA and polypeptide levels were approximately threefold higher in 786-O VHL cells than in 786-O Neo cells. In contrast, Cl-/HCO3- exchange activity in 786-O VHL cells was 50% lower than in 786-O Neo cells. Since resting intracellular pH (pH(i)) values were indistinguishable, we postulated that Na+/H+ exchange activity (NHE) might be similarly reduced in 786-O VHL cells. NHE-mediated pH(i) recovery from acid load was less than 50% that in 786-O Neo cells, whereas hypertonicity-stimulated, amiloride-sensitive NHE was indistinguishable in the two cell lines. The NHE3 mRNA level was higher in 786-O VHL than 786-O Neo cells, but NHE1 mRNA levels did not differ. AE2 and NHE3 are the first transcripts reported to be upregulated by pVHL. Elucidation of mechanisms responsible for downregulation of both ion exchange activities will require further investigation.