The Regulation of Nuclear Receptor Coactivator SRC-3 Activity Through Membrane Receptor Mediated Signaling Pathways
BAYLOR COLL OF MEDICINE HOUSTON TX
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SRC-3 interacts with steroid receptors in a ligand-dependent manner to activate receptor mediated transcription. A number of signaling pathways initiated by growth factors and hormones induce phosphorylation of SRC-3, regulating its function and contributing to its oncogenic potential. However, the range of mechanisms by which phosphorylation affects coactivator function remains largely undefined. We demonstrate here that the peptidyl-prolyl isomerase 1 Pin1, which catalyzes the isomerization of phosphorylated SerThr-Pro peptide bonds to induce conformational changes of its target proteins, interacts selectively and specifically with phosphorylated SRC-3. In addition, Pin1 and SRC-3 activate nuclear receptor regulated transcription synergistically. We present evidence that Pin1 modulates interactions between SRC-3 and CBPp300. Depletion of Pin1 in NCF-7 human breast cancer cells reduces endogenous estrogen-dependent recruitment of p300 to the promoters of estrogen receptor-dependent genes. Our results suggest that Pin1 functions as a transcriptional coactivator of nuclear receptors by modulating SRC-3 coactivator protein-protein complex formation, and ultimately, by regulating the turnover of the activated SRC-3 oncoprotein.
- Medicine and Medical Research