Regulatory pathways and role of VPF/VEGF in renal cancer

VPF/VEGF在肾癌中的调控通路及作用

• 批准号: 6782248
• 负责人: DEBABRATA MUKHOPADHYAY
• 金额: $ 29.26万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-11 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6782248
• 关键词: RNA binding protein; RNA interference; Von Hippel Lindau syndrome; angiogenesis; athymic mouse; biological signal transduction; cell growth regulation; enzyme activity; gene expression; genetic regulation; hypoxia inducible factor 1; messenger RNA; neoplasm /cancer blood supply; neoplasm /cancer genetics; posttranslational modifications; protein kinase C; protein protein interaction; protein structure function; proteomics; renal cell carcinoma; transcription factor; tumor suppressor genes; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Angiogenesis plays a pivotal role in several important pathological disease processes as well as in normal physiology. It is widely anticipated that modulation of angiogenesis (inhibition in tumors, stimulation in vascular insufficiency) will provide important therapeutic benefits. Like many human carcinomas, renal cell carcinomas (RCC), which are characteristically highly vascular, are thought to induce angiogenesis by secreting an angiogenic cytokine: vascular permeability factor, also known as vascular endothelial growth factor (VPF/VEGF). The long-term goal of this proposal is to investigate in depth the regulatory role of VPF/VEGF in RCC. RCC, arising sporadically or in the von Hippel Lindau (VHL) syndrome, exhibits loss of function of a tumor suppressor gene, VHL. Previously, our laboratory as well as others have shown that wild type VHL (pVHL) selectively interacts with and thereby down-regulates the activities of PKCzeta and Sp-1 and also degrades alpha subunits of hypoxia inducible factors (HIFs); when pVHL is afunctional, as in RCC, VPF/VEGF is over-expressed. But the mechanism of VPF/VEGF over-expression in the absence of pVHL is not yet clear. In Aim 1, we will study how PKC zeta interplays with HIF alphas, p300 and other transcription factors as well as trans-inhibitors like FIH. The endogenous promoter activity of VPF/VEGF will also be examined in RCCs in regard to PKC zeta and its regulators. In Aim 2, we will investigate the mechanism of VPF/VEGF mRNA stability in RCCs. We will examine the involvement of PKC zeta and its associated molecules in the modulation of RNA-binding protein, HuR, that usually binds at 3'-translated regions of VPF/VEGF mRNA. This aim will also elucidate the physical interactions between HuR and pVHL and its biological relevance. Finally, Aim 3 will extrapolate tissue culture data and reagents to animal models of RCC, seeking to understand the importance of VPF/VEGF as well as the mechanisms by which VPF/VEGF is activated in renal tumors; it is likely that we will propose new, specific targets for therapies that block angiogenesis and thereby tumor growth and metastasis. These experiments will provide new and important information on the mechanisms of carcinogenesis and suggest new targets for intervention in RCC, a common, highly vascular, angiogenesis-dependent carcinoma that is resistant to currently available therapies.

描述（由申请人提供）：血管生成在几种重要的病理疾病过程以及正常生理学中发挥着关键作用。人们普遍预计，血管生成的调节（抑制肿瘤、刺激血管功能不全）将提供重要的治疗益处。与许多人类癌症一样，肾细胞癌（RCC）具有高度血管化的特征，被认为通过分泌血管生成细胞因子：血管通透性因子，也称为血管内皮生长因子（VPF/VEGF）来诱导血管生成。该提案的长期目标是深入研究VPF/VEGF在RCC中的调节作用。偶发性肾细胞癌或因冯·希佩尔·林道 (VHL) 综合征引起的肾细胞癌表现出肿瘤抑制基因 VHL 功能的丧失。此前，我们的实验室和其他实验室已经表明，野生型VHL (pVHL) 选择性地与PKCzeta 和Sp-1 相互作用，从而下调它们的活性，并降解缺氧诱导因子(HIF) 的α 亚基；当 pVHL 功能障碍时，如肾细胞癌，VPF/VEGF 会过度表达。但在没有pVHL的情况下VPF/VEGF过度表达的机制尚不清楚。在目标 1 中，我们将研究 PKC zeta 如何与 HIF α、p300 和其他转录因子以及 FIH 等反式抑制剂相互作用。还将在 RCC 中检查 VPF/VEGF 的内源启动子活性，了解 PKC zeta 及其调节因子。在目标 2 中，我们将研究 RCC 中 VPF/VEGF mRNA 稳定性的机制。 我们将研究 PKC zeta 及其相关分子在 RNA 结合蛋白 HuR 调节中的参与情况，HuR 通常结合在 VPF/VEGF mRNA 的 3' 翻译区。这一目标还将阐明 HuR 和 pVHL 之间的物理相互作用及其生物学相关性。最后，目标 3 将组织培养数据和试剂外推至 RCC 动物模型，寻求了解 VPF/VEGF 的重要性以及 VPF/VEGF 在肾肿瘤中激活的机制；我们很可能会提出新的、具体的治疗靶标，以阻止血管生成，从而阻止肿瘤生长和转移。这些实验将提供关于致癌机制的新的重要信息，并提出干预 RCC 的新靶点。 RCC 是一种常见的、高度血管化、血管生成依赖性的癌症，对目前可用的疗法有耐药性。