Control of Prostate-Specific Gene Expression

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DESCRIPTION (provided by applicant): Understanding the mechanism that controls prostate-specific gene expression has already resulted in the identification of FoxA1 as an important co-regulator of AR action as well as prostate development. We have now demonstrated that USF2 interacts with FoxA1 on multiple prostate-specific promoters. This indicates that USF2 functions to promote expression of genes associated with differentiation consistent with previously reported mechanism whereby USF2 inhibits proliferation by down regulating c-myc. Controlling prostate- specific gene expression with a complex of AR (signal dependent), FOXA1 (developmental cell specific for endoderm) and USF2 (differentiation specific) reveals a remarkable coming together of regulatory factors to dictate prostate-specific gene expression. Continuing work using tagged FOXA1 for affinity purification followed with Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS) has identified 16 nuclear proteins that met the requirement of at least two peptide hits per protein in two separate experiments. Of these, 7 nuclear proteins can be either directly or indirectly linked to AR/FOXA1 action. Determining the factors that control prostate-specific gene expression has important implications for the understanding of cell fate during prostate development, androgen regulation of prostate disease, as well as understanding the fundamental cascade that controls cell determination and cell differentiation. Based upon published and our preliminary data, our Hypothesis is that by identifying the TFs that control prostate-specific gene expression, we are also identifying TF that play a critical role in prostate development. Three specific aims are proposed: Aim 1: To characterize the transcription factor complex of AR-regulated prostate-specific genes; Aim 2: To identify novel FOXA1 binding partners by tandem affinity purification followed with Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS); Aim 3: To determine the function of identified TFs in prostate development and androgen dependence. Determining the remaining TFs that control prostate-specific gene expression has important implications for the understanding the factors that control androgen regulation of prostatic diseases such as hBPH and PCa.