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.
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