VEGF TRANSCRIPTIONAL REGULATION BY TUMOR SUPPRESSOR VHL

肿瘤抑制因子 VHL 对 VEGF 转录的调控

• 批准号: 2733434
• 负责人: HERBERT TOD COHEN
• 金额: $ 31.63万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2733434
• 关键词: gene expression; genetic promoter element; genetic regulation; genetic regulatory element; genetic transcription; kidney cell; molecular oncology; tissue /cell culture; tumor suppressor genes; vascular endothelial growth factors

DESCRIPTION: (adapted from the investigator's abstract) Clear-cell renal cancer is a major clinical problem. It accounts for 85 percent of all renal cancers and 11,000 deaths annually in the US. The VHL gene was cloned in 1993 as the causative gene for von Hippel-Lindau disease, a rare inherited disorder characterized by several types of vascular tumors, including clear-cell renal cancer. Most importantly, VHL is now recognized as the causative gene for sporadic clear-cell renal cancer as well, providing a critical starting point for elucidating this common neoplasm's molecular pathogenesis. The applicant, a new investigator applying for initial independent funding, has shown in a recent Mol Cell Biol paper that VHL normally represses transcription of the vascular endothelial growth factor (VEGF) gene and that a major part of the mechanism involves a VEGF VHL-responsive cis element. Part of this effect is due to VHL directly binding Sp1 and inhibiting Sp1 activity. The applicant has since mapped the VHL Sp1-binding domain to a VHL minor mutational hot spot, which he has found is also responsible for VHL self-association. Nevertheless, substantial evidence indicates hat the VHL-Sp1 interaction accounts for only about 20 percent of the VHL effect on the VEGF promoter. The remaining 80 percent is likely due to another VHL-mediated, or "target," transcription factor (VTTF) that acts through the VEGF cis element. They therefore propose the following Aims: Aim 1: Determination of the biological significance of the VHL 96-122 domain (and the VHL-Sp1 and VHL-VHL interactions) Aim 2: Characterization of the VHL-responsive cis element and identification of he corresponding transfactor Aim 3: Characterization of the VHL transcriptional repression domain and identification of a VHL cofactor By narrowing these regions, the applicant expects to identify the VTTF, which may be a VHL corepressor, or a non-Sp1 transcriptional activator inhibited by VHL. A VHL corepressor may even be encoded by a renal cancer gene. As a transcription factor, the VTTF may affect expression of a large subset of target genes, and defining what constitutes a VHL- responsive element may aid in their identification. The VTTF and this VHL effector pathway may also have importance in vascular and renal development, and in other disease contexts, such as renal cystic disease and diabetic retinopathy.

描述：（改编自研究者摘要）肾透明细胞 癌症是一个主要的临床问题。它占到了85% 肾癌和11，000死亡每年在美国。VHL基因是 在1993年克隆作为冯希佩尔-林道病的致病基因， 一种罕见的遗传性疾病，以几种类型的血管为特征 肿瘤，包括肾透明细胞癌。最重要的是，VHL现在 被认为是散发性透明细胞肾癌的致病基因 同时，为阐明这一共同点提供了一个关键的起点， 肿瘤的分子发病机制。申请人，一名新的调查员 申请初始独立资金，在最近的Mol Cell VHL通常抑制血管内皮细胞的转录， 血管内皮生长因子（VEGF）基因， 该机制涉及VEGF VHL-响应性顺式元件。部分 这种作用是由于VHL直接结合Sp1并抑制Sp1活性。 此后，申请人将VHL Sp1结合结构域映射到VHL次要结构域 突变热点，他发现这也是VHL的原因 自我联想然而，大量证据表明， VHL-Sp1相互作用仅占VHL效应的20 在VEGF启动子上。剩下的80%可能是由于另一个 VHL介导的或“靶向”转录因子（VTTF），其通过以下途径起作用： VEGF顺式元件。因此，他们提出以下目标： 目的1：确定VHL 96-122的生物学意义 结构域（以及VHL-Sp1和VHL-VHL相互作用） 目的2：VHL响应性顺式元件的表征和 相应转移因子鉴定 目的3：VHL转录抑制结构域的表征和 VHL辅因子鉴定 通过缩小这些区域，申请人期望确定VTTF， 其可以是VHL辅阻遏物或非Sp1转录激活物 被VHL抑制。VHL辅阻遏物甚至可以由肾细胞内的 癌症基因作为一种转录因子，VTTF可能影响表达 一个大的靶基因子集，并定义什么构成VHL- 响应元件可以帮助它们的识别。VTTF和这个 VHL效应子通路也可能在血管和肾脏疾病中具有重要意义。 发展，以及其他疾病的情况下，如肾囊肿 和糖尿病视网膜病变。