Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene
Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene
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DOI：
10.1073/pnas.93.20.10589
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发表时间：
1996-10-01
影响因子：
11.1
通讯作者：
Linehan, WM
中科院分区：
文献类型：
--
作者：
Gnarra, JR;Zhou, SB;Linehan, WM
VHL肿瘤抑制基因在von Hippel-Lindau病和大多数散发性透明细胞肾癌患者中失活。虽然VHL蛋白的功能尚不清楚，但VHL在体内确实与延伸蛋白BC亚基相互作用，并通过抑制延伸蛋白ABC复合物的形成来调节RNA聚合酶II的体外延伸活性。在具有失活内源性VHL的肾癌细胞中表达野生型VHL导致体外细胞生长不变，血管内皮生长因子（VEGF）mRNA表达和对血清剥夺的反应性降低。VEGF在许多肿瘤中高度表达，包括VHL相关和散发性肾癌，并且它刺激生长中的实体瘤中的新血管生成。尽管VEGF mRNA水平有5倍的差异，VHL过表达并不影响VEGF转录的起始或延长，正如VHL-延长蛋白相关性所表明的那样。这些结果表明，VHL调节VEGF的表达在转录后水平和VHL失活的靶细胞导致VEGF抑制的损失，导致血管基质的形成。
The VHL tumor suppressor gene is inactivated in patients with von Hippel-Lindau disease and in most sporadic clear cell renal carcinomas. Although VHL protein function remains unclear, VHL does interact with the elongin BC subunits in vivo and regulates RNA polymerase II elongation activity in vitro by inhibiting formation of the elongin ABC complex, Expression of wild-type VHL in renal carcinoma cells with inactivated endogenous VHL resulted in unaltered in vitro cell growth and decreased vascular endothelial growth factor (VEGF) mRNA expression and responsiveness to serum deprivation. VEGF is highly expressed in many tumors, including VHL-associated and sporadic renal carcinomas, and it stimulates neoangiogenesis in growing solid tumors. Despite 5-fold differences in VEGF mRNA levels, VHL overexpression did not affect VEGF transcription initiation or elongation as would have been suggested by VHL-elongin association. These results suggest that VHL regulates VEGF expression at a post-transcriptional level and that VHL inactivation in target cells causes a loss of VEGF suppression, leading to formation of a vascular stroma.