Novel Targets of the Von Hippel Lindau Gene

描述：(申请人提供)对肿瘤的监管 转化、信使核糖核酸的转换和对低氧的适应性反应都是 具有深远的生物学和临床重要性。这些明显不同的细胞 这些事件通过单个蛋白质Von的功能联系在一起 Hippel-Lindau(VHL)基因产物pVHL。肾细胞癌(RCC)相关 VHL突变患者葡萄糖转运蛋白1(GLUT)表达增加 1)和血管内皮生长因子(VEGF)mRNA，其结果是 提高了mRNA的稳定性和转录水平。VHL基因的相互作用 含有细长蛋白B、C、Cu12和Rbx的产物pVHL-L已经确凿地证明 这种复合体(VBC)在调节蛋白质周转中的作用。然而， 肾细胞癌中pVHL的缺失也与激活 磷脂酰肌醇3(PI 3)-激酶通路与紊乱纤维连接蛋白(FN) 集合。这两种观察结果都不能解释 PVHL缺陷型低氧诱导的血管内皮生长因子和可能的GLUT1基因 RCC线路。我们有四个观察结果，可能会发现 PVHL基因缺陷肾癌细胞GLUT1mRNA稳定性增强的机制(S) 行数： I)GLUT1 3‘非编码区以pVHL依赖的方式改变基因表达； Ii)pVHL特异性调节hnRNP A2的表达，从而结合 Glut1 3‘非编码区； Iii)pVHL对hnRNP A2水平的调节需要有功能的蛋白酶体； Iv)pVHL调节p38应激激活蛋白激酶(SAPK)的激活，这是 调节血管内皮生长因子和其他Aure依赖的mRNA周转。 我们假设pVHL的缺失导致了p38的激活。 SAPK通路和hnRNP A2的过表达及其意义 与GLUT1 mRNA周转率的相关性。

DESCRIPTION: (provided by applicant) The regulation of neoplastic transformation, mRNA turnover, and the adaptive response to hypoxia are each of profound biologic and clinical importance. These apparently distinct cellular events are linked through the function of a single protein, the Von Hippel-Lindau (VHL) gene product, pVHL. Renal cell carcinomas (RCC) associated with VHL mutations exhibit increased expression of Glucose Transporter 1 (GLUT 1) and Vascular Endothelial Growth Factor (VEGF) mRNA, which results from increased mRNA stability and transcription. The interaction of the VHL gene product, pVHL, with elongin B, C, Cu12, and Rbx-l has conclusively demonstrated a role of this complex (VBC) in regulating protein turnover. However, the absence of pVHL in RCC cells has also been associated with activation of the phosphatidylinositol 3 (PI 3)-kinase pathway, and disordered fibronectin (FN) assembly. Neither observation accounts for the increased stability of hypoxia-inducible (VEGF and possibly GLUT1) mRNA observed with pVHL-deficient RCC lines. We have made four observations that potentially identify mechanism(s) of increased GLUT1 mRNA stability in pVHL deficient RCC cell lines: i) The GLUT1 3'UTR alters gene expression in a pVHL-dependent manner; ii) pVHL specifically regulates the expression of hnRNP A2, which binds the GLUT1 3'UTR; iii) Regulation of hnRNP A2 levels by pVHL requires functioning proteasomes; iv) pVHL regulates p38 Stress-Activated Protein Kinase (SAPK) activation, which modulates VEGF and other AURE-dependent mRNA turnover. We hypothesize that the absence of pVHL results in the activation of the p38 SAPK pathway and hnRNP A2 overexpression and propose to address this and its relevance to GLUT1 mRNA turnover.