Direct functional interactions between insulin-like growth factor-binding protein-3 and retinoid X receptor-α regulate transcriptional signaling and apoptosis

Insulin-like growth factor-binding protein (IGFBP)-3 regulates apoptosis in an IGF-independent fashion and has been shown to localize to nuclei. We cloned the nuclear receptor retinoid X receptor-alpha>(*) over bar * (RXR-alpha) as an IGFBP-3 protein partner in a yeast two-hybrid screen. Multiple methodologies showed that IGFBP-3 and RXR-alpha bind each other within the nucleus. IGFBP-3-induced apoptosis was abolished in RXR-alpha -knockout cells. IGFBP-3 and RXR ligands mere additive in inducing apoptosis in prostate cancer cells. IGFBP-3 enhanced RXR response element and inhibited RARE signaling. Thus, RXR-alpha -IGFBP-3 interaction leads to modulation of the transcriptional activity of RXR-alpha and is essential for mediating the effects of IGFBP-3 on apoptosis.