Transforming growth factor-betas (TGF-betas) are 25 kDa multifunctional autocrine/paracrine peptides with potent activity on growth suppression and apoptosis of epithelial cells. In the prostate, expression of TGF-beta protein and their receptors are induced upon androgen ablation, coincident with apoptotic cell death that occurs concomitantly in this tissue. Prostatic cells lose dependence on androgens and become resistant to TGF-beta responses during carcinogenesis, through mechanisms that remain to be defined. Further support for a tumor suppressor role of TGF-beta in the prostate comes from studies where we ablated TGF-beta signaling in two non-tumorigenic cell lines (NRP-152 and DP-153) by retroviral transduction of a dominant-negative TbetaRII, and showed the consequent loss of response to TGF-beta triggers malignant transformation. Loss of TGF-beta receptor expression is one of many potential mechanisms of TGF-beta resistance. Other pathways may involve activation of certain oncogenes that intercept TGF-beta signals at various levels. We have recently reported that DHT can directly block TGF-beta signaling through an association between AR and Smad3, leading to the transcriptional inactivation of Smad3 in LNCaP and NRP-154 prostatic epithelial cells. We provide evidence using EMSAs that AR's inhibitory effect is through blocking the binding of Smad3 to Smad Binding Elements (SBE) of target genes. Here we propose to investigate:1) the effects of DHT/AR on growth arrest and apoptosis induced by TGF-beta (or active Smad3), 2) expression of TGF-beta inducible genes by DHT/AR, 3) the structure/functional basis behind the binding of AR to Smad3, 4) possible function of AR co-activators as co-regulators or Smad3 through AR, and 5) differences in the interaction of AR with Smad3 in various nontumorigenic and tumorigenic cell lines. We believe these studies will most certainly impact on the therapeutic intervention of prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Cell Biology Study Section (TCB)
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Sathyamoorthy, Neeraja
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Case Western Reserve University
Internal Medicine/Medicine
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United States
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Shankar, Eswar; Song, Kyung; Corum, Sarah L et al. (2016) A Signaling Network Controlling Androgenic Repression of c-Fos Protein in Prostate Adenocarcinoma Cells. J Biol Chem 291:5512-26
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