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Estrogen Receptor-Mediated Down-Regulation of Corticotropin-Releasing Hormone Gene Expression Is Dependent on a Cyclic Adenosine 3',5'-Monophosphate Regulatory Element in Human Placental Syncytiotrophoblast Cells

Department of Physiology (X.N., Y.H., X.T.), Second Military Medical University, Shanghai 200433, People’s Republic of China; and Mothers and Babies Research Center (B.R.K., M.A.R., R.S., R.C.N.), Hunter Medical Research Institute, University of Newcastle, New South Wales 2310, Australia

Address all correspondence and requests for reprints to: Dr. Richard C. Nicholson, Mothers and Babies Research Center, Endocrine Unit, John Hunter Hospital, Locked Bag 1, Hunter Region Mail Center, New South Wales 2310, Australia. E-mail: rick.nicholson{at}hunter.health.nsw.gov.au.

Placental CRH plays a major role in the mechanisms controlling human pregnancy and parturition. Understanding how placental CRH production is regulated is therefore of importance. Previously we have shown that placental expression of CRH peptide and mRNA are inhibited by estrogens, in contrast to the stimulatory effects of estrogen on hypothalamic CRH production. Our current study found that in placental cells cotransfected with a CRH promoter construct and an estrogen receptor- expression vector results in a differential regulation whereby 17ß-estradiol (E2) decreased and the putative pure estrogen antagonist, ICI 182780, increased CRH promoter activity. Sequential deletion of the CRH promoter indicated that the region between –248 and –213 bp was essential for the effect of both E2 and ICI 182780. This region contains a consensus cAMP regulatory element (CRE) that is a requirement for E2- and ICI 182780-mediated activity because the CRE motif can confer E2 inhibition on a heterologous promoter such as rabbit ß-globin. Mutation of the CRE resulted in a complete reversal of E2 and ICI 182780 regulatory effects. In summary, our results demonstrate that a consensus CRE is required for the action of estrogen receptor ligands in human placental syncytiotrophoblast cells.

This work was supported by the Natural Science Foundation of China Grants 39870300 and 30270511 (to X.N.) and the National Health and Medical Research Council of Australia (to R.S., R.C.N.).

Abbreviations: AP-1, Activator protein-1; CRE, cAMP response element; E2, 17ß-estradiol; ER, estrogen receptor; ERE, estrogen response element; FCS, fetal calf serum.

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