TR4 ORPHAN RECEPTOR IN TESTIS

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DESCRIPTION: The testicular orphan receptor 4 (TR4) was initially cloned from prostate and testes cDNA libraries by the P.I.(Chang et al, 1994). Preliminary studies indicated that the TR4 might belong to the estrogen receptor/thyroid receptor nuclear receptor subfamily due to its ability to bind to AGGTCA direct repeats. Functional analysis showed that the TR4 could suppress retinoic acid (RA)-induced transactivation, recognize a DNA promoter in HIV-I and SV40, and induce the CNTFR gene expression. The TR4 can also modulate the thyroid hormone, Vitamin D, and PPARalpha signal cascades, and exert negative activity on erythropoietin gene expression. Our preliminary data found that ligands for RXR, PPARalpha, and CNTFR could also control the expression of the TR4, providing a bi-directional feedback, control mechanism between TR4 and other signaling pathways. Based on the above data, the investigators propose the following 5 aims to further characterize the TR4 in the prostate and testis. Aim 1) Isolation of cofactors (coactivators/corepressors) that can modulate the TR4 functions. Aim 2) 5' promoter characterization and isolation of cis-acting elements that control expression of the TR4. Aim 3) Isolation of trans-acting factors (TAFs) that control expression of the TR4. Aim 4) Identification of ligands or activators for TR4. Aim 5) Study cross talk between p53 and TR4 in testes. The successful completion of this proposal may help us to better understand the molecular mechanism of the TR4 and its potential biochemical functions.