Novel Targets of the Von Hippel Lindau Gene

Von Hippel Lindau 基因的新靶标

• 批准号: 6623380
• 负责人: WILLIAM FREDERICK CARSON RIGBY
• 金额: $ 28.12万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-22 至 2007-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623380
• 关键词: JUN kinase; SDS polyacrylamide gel electrophoresis; Von Hippel Lindau syndrome; antiserum; autoradiography; cell line; complementary DNA; gel electrophoresis; gene expression; gene mutation; glucose transporter; heterogeneous nuclear ribonucleoprotein; immunoprecipitation; messenger RNA; northern blottings; polymerase chain reaction; protease inhibitor; proteasome; protein protein interaction; radiotracer; renal cell carcinoma; transfection /expression vector; tumor suppressor proteins; vascular endothelial growth factors; western blottings

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.

描述：（由申请人提供）肿瘤的调节 转化，mRNA转换和对缺氧的自适应反应是 深刻的生物学和临床重要性。这些明显不同的细胞 事件通过单个蛋白质的功能链接 Hippel-Lindau（VHL）基因产品PVHL。肾细胞癌（RCC）相关 随着VHL突变表现出增加葡萄糖转运蛋白1的表达（Glut） 1）和血管内皮生长因子（VEGF）mRNA，这是由 提高mRNA稳定性和转录。 VHL基因的相互作用 产品，PVHL，带有Elongin B，C，Cu12和RBX-L的产品最终证明了 该复合物（VBC）在调节蛋白质更新中的作用。但是， RCC细胞中缺乏PVHL也与激活有关 磷脂酰肌醇3（PI 3） - 激酶途径和无序纤连蛋白（FN） 集会。两者都没有观察到提高的稳定性 缺乏PVHL缺乏症状的缺氧（VEGF和可能的GLUT1）mRNA RCC线。我们进行了四个可能识别的观察 PVHL缺乏RCC细胞中GLUT1 mRNA稳定性增加的机制 线： i）Glut1 3'Utr以PVHL依赖性方式改变基因表达； ii）PVHL明确调节HNRNP A2的表达，该表达结合了 glut1 3'utr; iii）通过PVHL调节HNRNP A2水平需要功能蛋白酶体； iv）PVHL调节P38应激激活的蛋白激酶（SAPK）激活，该激活 调节VEGF和其他依赖Aure的mRNA更新。 我们假设缺乏PVHL导致p38的激活 SAPK途径和HNRNP A2过表达，并提议解决此问题及其 与GLUT1 mRNA转换相关。