Peptidyl-prolyl isomerase 1 (Pin1) serves as a coactivator of steroid receptor by regulating the activity of phosphorylated steroid receptor coactivator 3 (SRC-3/AIB1).
Steroid receptor coactivator 3 (SRC-3/AIB1) interacts with steroid receptors in a ligand-dependent manner to activate receptor-mediated transcription. A number of intracellular 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 peptidyl-prolyl isomerase 1 (Pin1), which catalyzes the isomerization of phosphorylated Ser/Thr-Pro peptide bonds to induce conformational changes of its target proteins, interacts selectively with phosphorylated SRC-3. In addition, Pin1 and SRC-3 activate nuclear-receptor-regulated transcription synergistically. Depletion of Pin1 by small interfering RNA (siRNA) reduces hormone-dependent transcription from both transfected reporters and an endogenous steroid receptor target gene. We present evidence that Pin1 modulates interactions between SRC-3 and CBP/p300. The interaction is enhanced in vitro and in vivo by Pin1 and diminished when cellular Pin1 is reduced by siRNA or in stable Pin1-depleted cell lines. Depletion of Pin1 in MCF-7 human breast cancer cells reduces the endogenous estrogen-dependent recruitment of p300 to the promoters of estrogen receptor-dependent genes. Pin1 overexpression enhanced SRC-3 cellular turnover, and depletion of Pin1 stabilized SRC-3. 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 also promoting the turnover of the activated SRC-3 oncoprotein.
Yi
Ping
P
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Wu
Ray-Chang
RC
Sandquist
Joshua
J
Wong
Jiemin
J
Tsai
Sophia Y
SY
Tsai
Ming-Jer
MJ
Means
Anthony R
AR
O'Malley
Bert W
BW
D000123:Acetyltransferases / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D004967:Estrogens / Q000502:physiology; D051548:Histone Acetyltransferases; D006801:Humans; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D000596:Amino Acids; D004967:Estrogens; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D011987:Receptors, Steroid; D015534:Trans-Activators; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3; D050880:p300-CBP Transcription Factors; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse