Direct functional interactions between insulin-like growth factor-binding protein-3 and retinoid X receptor-alpha 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(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 were 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.
Liu
B
B
Department of Pediatrics, University of California, Los Angeles, California 90095-1752, USA.
Lee
H Y
HY
Weinzimer
S A
SA
Powell
D R
DR
Clifford
J L
JL
Kurie
J M
JM
Cohen
P
P
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D019556:COS Cells; D003001:Cloning, Molecular; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000502:physiology*; D008969:Molecular Sequence Data; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D020218:Response Elements; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
D018972:Insulin-Like Growth Factor Binding Protein 3; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors