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Mechanisms Down-Regulating Sprouty1, a Growth Inhibitor in Prostate Cancer

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Annual rept. 20 Sep 2004-19 Sep 2005

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The Sprouty gene family negatively regulates growth factor-induced receptor tyrosine kinase signaling. I have demonstrated that Sprouty1 and 4 are down-regulated in human prostate cancers. The purpose off the present study is to elucidate the molecular mechanisms regulating Sprouty expression in prostate cancer. I have carried out DNA methylation analysis on 20 matched normal prostate tissues and tumor prostate tissues at least 70 of tissue is carcinoma in the 5 untranslated region of Sprouty1 and 4 genes. Results show hypermethylation of the Sprouty4 in prostate cancer tissues more than half of all prostate cancer DNAs were methylated in this region and methylation significantly correlated with decrease in Sprouty4 expression as determined by quantitative RT-PCR. Methylation analysis of Sprouty1 5 untranslated region is currently being investigated. To investigate The transcriptional regulation of Sprouty1 in prostate cancer, I have identified transcription start sites in 5RACE reaction and characterized the Sprouty1 promoter region. Transient transfections using luciferase reporter gene constricts with progressive deletions of the human Sprouty1 5-flanking region revealed that the core promoter activity is located within The proximal 0.3-Kb region. Comparative analysis of The 5-flanking region of The human and mouse Sprouty1 shows a highly conserved binding site for Wt1, a transcription factor involved in renal development and tumorigenesis suggesting That Wt1 may be a key transcriptional regulator in Sprouty1 gene expression. Work is currently underway to identity the transcription factors binding to this core promoter region using a novel protein-DNA interaction based method. My studies suggest a potential tumor suppressor activity of Sprouty1 and 4 in prostate cancer. Complete elucidation of the molecular mechanisms controlling Sprouty expression may prove useful iii understanding the regulation of growth factor signaling in prostate cancer.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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