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Transcriptional Cofactors Exhibit Differential Preference toward Peroxisome Proliferator-Activated Receptors and in Uterine Cells

Departments of Obstetrics & Gynecology (H.J.L., I.M., K.H.) and Cell Biology & Physiology (H.J.L.), Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Dr. H. Jade Lim, Department of Obstetrics & Gynecology, Washington University School of Medicine, Campus Box 8064, 4566 Scott Avenue, St. Louis, Missouri 63110. E-mail: limj{at}wustl.edu.

We previously showed that peroxisome proliferator-activated receptor (PPAR) is crucial for embryo implantation as a receptor for cyclooxygenase-2-derived prostacyclin in mice. PPARs belong to the nuclear receptor superfamily. They form heterodimer with a retinoid X receptor, recruit transcriptional cofactors, and bind to a specific recognition element for regulation of target genes. Although cofactors are generally shared by various nuclear receptors, some are involved in cell-specific events. The objective of this investigation was to examine interactions of transcriptional cofactors with PPAR in uterine cells for its effectiveness in regulating gene expression. We chose two uterine cellular systems: periimplantation mouse uterus and AN₃CA human uterine cell line. As examined by in situ hybridization, steroid receptor coactivator (SRC)-2, SRC-3, PPAR-interacting protein, receptor-interacting protein 140 (RIP140), nuclear receptor corepressor (N-CoR), and silencing mediator for retinoid and thyroid hormone receptor (SMRT) exhibit overlapping expression with that of PPAR in the periimplantation mouse uterus. Glutathione-S-transferase (GST) pull-down assays show that PPAR physically interacts with SRC 1–3, RIP140, PPAR-binding protein, N-CoR, and SMRT in the absence of ligands, suggesting their potent interactions with PPAR. Transient transfection assays in AN₃CA cells show that among members of the SRC family, only SRC-2 serves as a true coactivator for PPAR, whereas all SRC members could enhance PPAR-induced transcriptional activation. Interestingly, N-CoR and SMRT potently repress PPAR-induced transcriptional activation but fail to repress PPAR activity. RIP140 is effective in repressing basal and PPAR-induced transcriptional activation. Collectively, the results suggest that gene regulation by PPAR in the uterine cells uniquely responds to SRC-2, N-CoR, SMRT, or RIP140, and these interactions may be operative during implantation when these cofactors are abundantly expressed.