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Epidermal Growth Factor Regulation of Equine Glycoprotein Hormone Subunit Expression in Trophoblast Cells¹

^a Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160-7401

ABSTRACT

Primates and equids are the only species known to express the placental glycoprotein hormone, chorionic gonadotropin (CG), a heterodimeric glycoprotein composed of an subunit linked to a hormone-specific ß subunit. The regulatory mechanisms involved in the induction of equine glycoprotein subunit gene expression have not been identified. Epidermal growth factor (EGF) receptor is known to transduce signals that alter a number of different cellular functions (cell proliferation, differentiation, hormone secretion, and gene regulation). In the present study, we investigated the regulation of the equine subunit gene by EGF in trophoblasts. We found that 2800 base pairs of 5' flanking sequence from the equine subunit promoter is sufficient for basal expression in human choriocarcinoma cells. Epidermal growth factor and phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC), increased transcriptional activity of the equine subunit promoter (-2800/+21). These responses were blocked by pretreatment with bisindolylmaleimide-I, an inhibitor of PKC, suggesting an involvement of this pathway downstream of EGF. In addition, PD98059, an inhibitor of the extracellular signal-regulated kinase (ERK) pathway, completely blocked activation of the equine promoter by PMA, suggesting that mitogen-activated protein kinase (MAPK) cascade was involved downstream of the PKC pathway. In conclusion, the EGF/PKC/MAPK pathway regulates equine glycoprotein subunit gene expression through a distinct regulatory region (-2300 to -1900) in trophoblasts, while essential elements for basal expression appear to exist within the -2800 to -1900 region of the promoter.

FOOTNOTES

First decision: 1 February 2001.

¹ This research was supported in part by a grant, R29 DK50668, from the National Institutes of Health (NIH) to M.W.W. and was facilitated by the Cell Culture and Imaging Cores of the NIH-supported Center of Reproductive Sciences (HD 33994) at the University of Kansas Medical Center. T.M.T. is supported in part by the W.S. Sutton Award and Biomedical Research Program fellowship at University of Kansas Medical Center.

² Correspondence: Michael W. Wolfe, Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160-7401. FAX: 913 588 7430;mwolfe2{at}kumc.edu

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