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
Xin Ni,
Yue Hou,
Bruce R. King,
Xiaolu Tang,
Mark A. Read,
Roger Smith and
Richard C. Nicholson
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 controllinghuman pregnancy and parturition. Understanding how placentalCRH production is regulated is therefore of importance. Previouslywe have shown that placental expression of CRH peptide and mRNAare inhibited by estrogens, in contrast to the stimulatory effectsof estrogen on hypothalamic CRH production. Our current studyfound that in placental cells cotransfected with a CRH promoterconstruct and an estrogen receptor- expression vector resultsin a differential regulation whereby 17ß-estradiol(E2) decreased and the putative pure estrogen antagonist, ICI182780, increased CRH promoter activity. Sequential deletionof the CRH promoter indicated that the region between –248and –213 bp was essential for the effect of both E2 andICI 182780. This region contains a consensus cAMP regulatoryelement (CRE) that is a requirement for E2- and ICI 182780-mediatedactivity because the CRE motif can confer E2 inhibition on aheterologous promoter such as rabbit ß-globin. Mutationof the CRE resulted in a complete reversal of E2 and ICI 182780regulatory effects. In summary, our results demonstrate thata consensus CRE is required for the action of estrogen receptorligands in human placental syncytiotrophoblast cells.
This work was supported by the Natural Science Foundation ofChina Grants 39870300 and 30270511 (to X.N.) and the NationalHealth and Medical Research Council of Australia (to R.S., R.C.N.).
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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. 
