25-10-2012, 10:49 AM
Orphan Receptor TR3/nur77 and Apoptosis in Prostate Cancer Cells
ABSTRACT
TR3 (also called Nur77 or NGFI-B), an immediate-early response gene and an orphan member of the nuclear receptor
superfamily, regulates both survival and death of prostate cancer cells. It is overexpressed in prostate tumor and acts in the
nucleus to promote tumor cell growth. In response to certain apoptotic stimuli, TR3 migrates from the nucleus to the cytoplasm
where it targets mitochondria to induce cytochrome C release and apoptosis. Translocation of TR3 from the nucleus to the
cytoplasm requires its heterodimerization with retinoid X receptor (RXR) and it is highly regulated by RXR ligands. In
addition, phosphorylation of TR3 protein modulates its subcellular localization and biological activities. Mitochondrial
localization of TR3 is mediated by its interaction with Bcl-2, a potent anti-apoptotic protein that is overexpressed in prostate
tumors. Binding of TR3 to Bcl-2 induces a Bcl-2 conformational change, resulting in conversion of Bcl-2 from a protector
to killer. These results establish a novel TR3-dependent apoptotic pathway in prostate cancer cells and its regulation. They also
demonstrate that TR3 is an attractive molecular target for developing new prostate cancer therapeutics.