This proposal is for the continuation of a research project in its 4th year of funding, with goals for the characterization of TR2 and TR3 orphan receptors (TR2 and TR3) in prostate cancer. TR2 and TR3 are members of the steroid receptor superfamily that were identified in the P.I.'s laboratory. Based on the past several years' research efforts from the labs of the P.I. and others, we now know TR2 and TR3 may represent master regulators in the prostate and other organs. Target genes and their hormone response elements (from DR1 to DR6) have been isolated and characterized. Data from the P.I.'s lab suggested that TR2 could modulate several important signaling pathways that may play vital roles in the prostate growth, such as (1) Retinoids- RAR/RXR-mediated apoptosis, (2) Vitamin D-VDR-mediated differentiation, and (3) irradiation-p53 -mediated apoptosis. The expression of some viruses (such as SV40 and HPV) can be regulated by TR2. The CNTF signaling pathway can also be regulated by TR2/TR3 expression. Expression of TR3 may be linked to the prostate cancer apoptosis (as demonstrated in LNCaP and PC-3 cells). Based on the above progress, we will propose the following 3 Aims to continue the characterization of TR2 and TR3 in prostate cancer cells:
Aim 1, Isolation of trans-acting factors (TAFs) that control expression of TR2 and TR3;
Aim 2, Isolation of cofactors (coactivators/corepressors) that can modulate the TR2/TR3 functions;
and Aim 3, To study if induction of TR3 may link to the apoptosis in human prostate tumor. The success of this proposal will not only allow us to better understand the molecular mechanism of TR2/TR3, it may also help us to find new signaling pathways in the prostate that may contribute to the development of new drugs/therapies for the battle against prostate cancer.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Margolis, Ronald N
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University of Rochester
Schools of Dentistry
United States
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Mu, Xiaomin; Yang, Lin; Chang, Chawnshang (2006) Stage dependent and androgen inductive expression of orphan receptor TR4 in rat testis. Biochem Biophys Res Commun 341:464-9
Xie, Shaozhen; Lin, Hui-Kuan; Ni, Jing et al. (2004) Regulation of interleukin-6-mediated PI3K activation and neuroendocrine differentiation by androgen signaling in prostate cancer LNCaP cells. Prostate 60:61-7
Inui, Shigeki; Lee, Yi-Fen; Chang, Eugene et al. (2003) Differential and bi-directional regulation between TR2/TR4 orphan nuclear receptors and a specific ligand mediated-peroxisome proliferator-activated receptor alpha in human HaCaT keratinocytes. J Dermatol Sci 31:65-71
Mu, Xiaomin; Chang, Chawnshang (2003) TR2 orphan receptor functions as negative modulator for androgen receptor in prostate cancer cells PC-3. Prostate 57:129-33
Kim, Eungseok; Xie, Shaozhen; Yeh, Shauh-Der et al. (2003) Disruption of TR4 orphan nuclear receptor reduces the expression of liver apolipoprotein E/C-I/C-II gene cluster. J Biol Chem 278:46919-26
Lin, Wen-Jye; Li, Jie; Lee, Yi-Fen et al. (2003) Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4. J Biol Chem 278:9353-60
Mu, Xiaomin; Chang, Chawnshang (2003) TR3 orphan nuclear receptor mediates apoptosis through up-regulating E2F1 in human prostate cancer LNCaP cells. J Biol Chem 278:42840-5
Shyr, Chih-Rong; Hu, Yueh-Chiang; Kim, Eungseok et al. (2002) Modulation of estrogen receptor-mediated transactivation by orphan receptor TR4 in MCF-7 cells. J Biol Chem 277:14622-8
Hu, Yueh-Chiang; Shyr, Chih-Rong; Che, Wenyi et al. (2002) Suppression of estrogen receptor-mediated transcription and cell growth by interaction with TR2 orphan receptor. J Biol Chem 277:33571-9
Shyr, Chih-Rong; Collins, Loretta L; Mu, Xiao-Min et al. (2002) Spermatogenesis and testis development are normal in mice lacking testicular orphan nuclear receptor 2. Mol Cell Biol 22:4661-6

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