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Functional Association of PR and CCAAT/Enhancer-Binding Protein ß Isoforms: Promoter-Dependent Cooperation between PR-B and Liver-Enriched Inhibitory Protein, or Liver-Enriched Activatory Protein and PR-A in Human Endometrial Stromal Cells

Institute of Reproductive and Developmental Biology, Imperial College School of Medicine, Hammersmith Hospital (M.C., J.J.B.), London, United Kingdom W12 0NN; IHF Institute for Hormone and Fertility Research, University of Hamburg (Y.P., R.K., B.G.), 22529 Hamburg, Germany

Address all correspondence and requests for reprints to: Dr Jan Brosens, Institute of Reproductive and Developmental Biology, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom W12 0NN. E-mail: j.brosens{at}ic.ac.uk

Activation of the decidual PRL (dPRL) promoter, a major differentiation marker in human endometrial stromal (ES) cells, by cAMP is effected through the induction and binding of CCAAT/enhancer-binding protein-ß (C/EBPß) to two overlapping cognate response elements in the promoter region dPRL-332/-270. Progesterone is essential for decidualization and potently enhances cAMP-dependent dPRL promoter activity. We now demonstrate that both liganded PR isoforms, PR-A and PR-B, are capable of trans-activating the dPRL-332/-270 region. The absence of a palindromic progesterone response element (PRE) within this promoter region suggested cross-coupling between C/EBPß and PR in human ES cells. Physical interaction between these distinct transcription factors was confirmed by glutathione-S-transferase pull-down assays, demonstrating that both C/EBPß isoforms, the full-length activator liver-enriched activatory protein (LAP) and the truncated inhibitor liver-enriched inhibitory protein (LIP), can bind PR-B as well as PR-A in vitro. Transient transfection studies in primary ES cells were used to examine the consequences of PR and C/EBPß interaction on activation of their respective response elements. Activation of mouse mammary tumor virus promoter or a reporter construct containing two isolated palindromic PREs by liganded PR-B was synergistically enhanced by coexpression of LIP, but not LAP. In contrast, PR-A failed to trans-activate these constructs significantly regardless of the presence of either C/EBPß isoform. Conversely, LAP-dependent activation of the dPRL-332/-270 region or a reporter construct driven by a single C/EBPß response element was greatly enhanced by PR-A, but not PR-B, in a ligand-dependent manner. These observations reveal that PR and C/EBPß isoform ratios are important determinants of the cellular response to ovarian progesterone in the reproductive tract; the predominance of PR-A and LAP favors expression of C/EBPß-dependent genes, whereas PR-B and LIP cooperate in activating PRE-driven promoters.

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