The focus of this proposal is on Androgen Receptor Trapped clone-27 (ART-27) and Unconventional prefoldin RBP5 Interactor (URI), two proteins that interact with one another and have a major impact on transcriptional regulation through the Androgen Receptor (AR). During prostate development in humans, ART-27 is expressed in differentiated luminal epithelial cells but is not detected in undifferentiated epithelial cell precursors, suggesting a role for ART-27 in AR-mediated growth suppression and differentiation. Consistent with a growth suppressive function, ART-27 expression levels are decreased in human prostate cancer and regulated expression of ART-27 in the androgen sensitive LNCaP prostate cancer cell line inhibits androgen- mediated cellular proliferation. Moreover, a somatic alteration in AR (AR P340L) derived from a prostate cancer shows diminished capacity to enhance ART-27 mediated AR-transcriptional activation. Further, a recent report and our two-hybrid results indicate that ART-27 associates with Unconventional prefoldin RBP5 Interactor (URI) forming complexes with RPB5, a subunit of RNA polymerase, to control transcription programs. URI is implicated in maintenance of genomic integrity and a recent profiling of staged cancer samples indicates that URI is one a group of genes up-regulated in Prostatic Intraepithelial Neoplasia (PIN), a proliferative lesion thought to be a precursor to prostate cancer. Based on these findings, we hypothesize that ART-27 is a cell type specific and developmentally regulated protein that links AR to the URI transcriptional regulatory complex and affects AR target genes important in prostate growth regulation. To test this hypothesis we propose to: 1) Identify ART-27-dependent AR- target genes and the impact of ART-27 and URI on cell cycle progression 2) Determine if ART-27 and URI function independently to direct AR-mediated gene transcription and 3) Elucidate the role of ART-27 in prostate epithelial cell growth and differentiation in vivo. The over-riding hypothesis of this proposal is that AR cofactors modulate specific programs of gene transcription that aid and abet tumor progression. ART-27 and URI are novel members of a transcription complex that clearly play an important role in AR signaling, yet very little is known about the function of these proteins in the prostate. The long-term goal is to understand how AR directs cell metabolism and differentiation in some cellular contexts and proliferation in others.

Public Health Relevance

While prostate cancers are initially treatable by anti-hormone therapy, they inevitably become resistant to therapy resulting in few treatment options. The focus of this grant is to understand the biology leading to anti- hormone resistant prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112226-05
Application #
8300227
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2008-09-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$341,161
Indirect Cost
$139,886
Name
New York University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Schneider, Jeffrey A; Logan, Susan K (2018) Revisiting the role of Wnt/?-catenin signaling in prostate cancer. Mol Cell Endocrinol 462:3-8
Briggs, Erica M; Ha, Susan; Mita, Paolo et al. (2018) Long interspersed nuclear element-1 expression and retrotransposition in prostate cancer cells. Mob DNA 9:1
Wang, Yu; Ledet, Russell J; Imberg-Kazdan, Keren et al. (2016) Dynein axonemal heavy chain 8 promotes androgen receptor activity and associates with prostate cancer progression. Oncotarget 7:49268-49280
Mita, Paolo; Savas, Jeffrey N; Briggs, Erica M et al. (2016) URI Regulates KAP1 Phosphorylation and Transcriptional Repression via PP2A Phosphatase in Prostate Cancer Cells. J Biol Chem 291:25516-25528
Wang, Yu; Garabedian, Michael J; Logan, Susan K (2015) URI1 amplification in uterine carcinosarcoma associates with chemo-resistance and poor prognosis. Am J Cancer Res 5:2320-9
Lee, Eugine; Ha, Susan; Logan, Susan K (2015) Divergent Androgen Receptor and Beta-Catenin Signaling in Prostate Cancer Cells. PLoS One 10:e0141589
Staverosky, Julia A; Zhu, Xin-Hua; Ha, Susan et al. (2013) Anti-androgen resistance in prostate cancer cells chronically induced by interleukin-1?. Am J Clin Exp Urol 1:53-65
Lee, Eugine; Madar, Aviv; David, Gregory et al. (2013) Inhibition of androgen receptor and ?-catenin activity in prostate cancer. Proc Natl Acad Sci U S A 110:15710-5
Imberg-Kazdan, Keren; Ha, Susan; Greenfield, Alex et al. (2013) A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells. Genome Res 23:581-91
Ha, S; Iqbal, N J; Mita, P et al. (2013) Phosphorylation of the androgen receptor by PIM1 in hormone refractory prostate cancer. Oncogene 32:3992-4000

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