Regulation of VEGF by WT1

Kent State University At Kent, Kent OH

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Abstract

DESCRIPTION (provided by applicant): The primary objective of this AREA proposal is to better understand how the Wilms' tumor suppressor gene (WT1) suppresses growth of LNCaP prostate cancer cells in vivo. Using cDNA microarrays, we observed that vascular endothelial growth factor, VEGF, was suppressed in the WT1 transfected LNCaP tumor cells (WT1-LNCaP) cells. Our hypothesis is that WT1 represses hormone induced VEGF transcription. This work is important because it will contribute to the understanding of 1) regulation of VEGF and 2) WT1 mediated tumor growth suppression. The long-term goal of this study will be to identify novel mechanisms of prostate tumor cell growth suppression and new approaches towards inhibition of angiogenesis. Additionally, this study provides a learning opportunity in the fundamentals of gene regulation for undergraduate students at Kent State University. We propose to: 1) use reporter assays to determine whether WT1 represses VEGF transcription in hormone treated cells and to disrupt that repression using WT1 targeted short inhibitory RNA (siRNA) 2) use EMSA and chromatin immunoprecipitation to determine whether WT1 repression of VEGF expression is mediated through DNA binding and 3) use immunohistochemistry of mouse tumor tissue sections to determine whether WT1 expression is inversely related to VEGF and angiogenesis.