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.

Public Health Relevance

Determining the factors that control androgen regulated 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055748-14
Application #
8434198
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Hoshizaki, Deborah K
Project Start
1999-09-30
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
14
Fiscal Year
2013
Total Cost
$320,909
Indirect Cost
$115,198
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Grabowska, Magdalena M; Elliott, Amicia D; DeGraff, David J et al. (2014) NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression. Mol Endocrinol 28:949-64
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Strand, Douglas W; DeGraff, David J; Jiang, Ming et al. (2013) Deficiency in metabolic regulators PPAR? and PTEN cooperates to drive keratinizing squamous metaplasia in novel models of human tissue regeneration. Am J Pathol 182:449-59
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Chen, Junwei; Guo, Tianhua; Zhang, Lei et al. (2012) CD133 and CD44 are universally overexpressed in GIST and do not represent cancer stem cell markers. Genes Chromosomes Cancer 51:186-95

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