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Characterization of a Human-Specific Regulator of Placental Corticotropin-Releasing Hormone

Departments of Obstetrics and Gynecology and Cell Biology and Physiology (S.A.) Washington University School of Medicine and the Division of Biology and Biomedical Sciences Program in Molecular and Cellular Biology (C.D.S., S.A.) Washington University St. Louis, Missouri 63110

The hypothalamic hormone CRH is also expressed in the placentas of humans and higher primates and may play an important role in the regulation of labor. In choriocarcinoma cell lines, activation of cAMP-dependent pathways increases human (h)CRH reporter gene expression. A cAMP-responsive region distinct from the cAMP response element at -220 bp, has been identified between -200 and -99 bp, and a candidate transcription factor was identified in nuclear extracts of human, but not rodent, choriocarcinoma cell lines.

This region, which does not contain a canonical cAMP response element (CRE), transfers protein kinase A responsiveness to a heterologous promoter. Electromobility shift assays and methylation and uracil interference studies localized factor binding to a 20-bp region from -128 to -109 bp of the hCRH promoter. This 20-bp fragment exhibited a similar shift in nuclear extracts from both human term placenta and from human JEG-3 cells. Base contacts, identified in interference studies, were confirmed as critical for binding, as a mutation of these bases abolished factor binding. Furthermore, a CRH promoter containing this mutation exhibited a diminished response to forskolin. UV cross-linking demonstrated the protein in nuclear extracts from human, but not rodent, choriocarcinoma cell lines and estimated its size as 58 kDa. Although this factor participates in cAMP-regulated gene expression, competition electrophoretic mobility assays demonstrated that the factor does not bind to a CRE. Furthermore, neither anti-CREB nor anti-ATF2 antibodies alter factor binding. These data identify this 58-kDa protein as the human-specific CRH activator previously identified as a candidate factor contributing to the species-specific expression of CRH in human placenta.

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