Novel Targets of the Von Hippel Lindau Gene

描述：（由申请人提供）肿瘤的调节 转化、mRNA周转和对缺氧的适应性反应分别是 具有深远的生物学和临床意义。这些明显不同的细胞 这些事件通过一种蛋白质的功能联系在一起， Hippel-Lindau（VHL）基因产物，pVHL。肾细胞癌（RCC）相关 VHL突变患者表现出葡萄糖转运蛋白1（GLUT）表达增加， 1)和血管内皮生长因子（VEGF）mRNA，其产生于 增加mRNA的稳定性和转录。VHL基因的相互作用 产物pVHL与延伸蛋白B、C、Cu 12和Rbx-1的结合已经决定性地证明了 这种复合物（VBC）在调节蛋白质周转中的作用。但 RCC细胞中pVHL的缺乏也与细胞内pVHL的激活有关。 磷脂酰肌醇3（PI 3）-激酶途径与纤维连接蛋白（FN）紊乱 组装件.这两种观察结果都不能解释 缺氧诱导的（VEGF和可能的GLUT 1）mRNA与pVHL缺陷 RCC线。我们做了四个观察， pVHL缺陷型RCC细胞中GLUT 1 mRNA稳定性增加的机制 线条： i）GLUT 1 3 'UTR以pVHL依赖性方式改变基因表达; ii）pVHL特异性地调节hnRNPA 2的表达，其结合pVHL。 GLUT 1 3'UTR; iii）pVHL对hnRNPA 2水平的调节需要功能性蛋白酶体; iv）pVHL调节p38应激活化蛋白激酶（SAPK）活化，其 调节VEGF和其他AURE依赖性mRNA周转。 我们假设pVHL的缺失导致p38的激活， SAPK途径和hnRNPA 2过表达，并提出解决这一问题及其 与GLUT 1 mRNA周转相关。

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.