VEGF TRANSCRIPTIONAL REGULATION BY TUMOR SUPPRESSOR VHL

描述：(改编自研究人员的摘要)透明细胞肾脏 癌症是一个主要的临床问题。占总人数的85%。 在美国，每年有11000人死于肾癌。VHL基因是 1993年被克隆为von Hippel-Lindau病的致病基因 罕见的遗传性疾病，以几种血管类型为特征 肿瘤，包括透明细胞肾癌。最重要的是，VHL现在是 被认为是散发性透明细胞肾癌的致病基因 也为阐明这一共同之处提供了一个关键起点 肿瘤的分子发病机制。申请人是一名新的调查员 申请最初的独立资金，在最近的一份Mol Cell中显示 VHL通常抑制血管转录的生物试纸 血管内皮细胞生长因子(VEGF)基因和 其作用机制涉及血管内皮生长因子VHL反应的顺式元件。其中的一部分 其作用机制可能与VHL直接结合Sp1，抑制Sp1活性有关。 申请人已经将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 自我关联。然而，大量证据表明， VHL-Sp1相互作用仅占VHL效应的20%左右 在血管内皮生长因子启动子上。剩下的80%很可能是由于另一个 VHL介导的或“靶向”转录因子(VTTF)通过 血管内皮生长因子顺式元件。因此，他们提出了以下目标： 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反应顺式元件的特性和 相应转铁蛋白的鉴定 目的3：VHL转录抑制结构域的特征和 一种VHL辅因子的鉴定 通过缩小这些区域，申请人期望识别VTTF， 其可以是VHL辅阻遏子或非Sp1转录激活子 被VHL抑制。VHL辅阻遏子甚至可以由肾脏编码 癌症基因。作为一种转录因子，VTTF可能会影响其表达 靶基因的一大子集，并定义什么构成VHL- 响应性元素可能有助于识别它们。VTTF和这个 VHL效应通路在血管和肾脏中也可能具有重要作用 在其他疾病的情况下，如肾囊性疾病 和糖尿病视网膜病变。

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.