title: Control of endothelin-a receptor expression by progesterone is enhanced by synergy with Gata2.
abstract: The endothelin-A receptor (Ednra) is involved in several physiological, pathological, and developmental pathways. Known for its function in vasoconstriction after being activated by endothelin-1, Ednra also controls cephalic neural crest cell development and appears to play a role in several pathologies, including cancer and periodontitis. However, the mechanisms regulating Ednra expression have not been identified despite its important functions. In this study, we investigated the role progesterone plays in Ednra gene expression in vivo and in vitro. In mice, pregnancy promotes Ednra expression in the heart, kidney, lung, uterus, and placenta, and the up-regulation is mediated by progesterone. We determined that the conserved region between -5.7 and -4.2 kb upstream of the mouse Ednra gene is necessary for the progesterone response. We also found that progesterone mediates Ednra activation through progesterone receptor B activation by its recruitment to PRE6, one of the 6 progesterone response elements found in that locus. However, gene activation by means of a GATA2 site was also necessary for the progesterone response. The Gata2 transcription factor enhances the progesterone response mediated by the progesterone receptor B. Together these results indicate that progesterone regulates Ednra expression by synergizing with Gata2 activity, a previously unknown mechanism. This mechanism may have an impact on pathologies involving the endothelin signaling.
authors.affiliation: Center for Craniofacial Research and Diagnosis and Department of Biomedical Sciences, Texas A&M University-Baylor College of Dentistry, Dallas, Texas 75246, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Knutsen
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Brown
authors.forename: L Bruno
authors.initials: LB
authors.lastname: Ruest
mesh_terms: D000818:Animals; D001483:Base Sequence; D005260:Female; D050989:GATA2 Transcription Factor / Q000502:physiology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011247:Pregnancy; D061251:Primary Cell Culture; D011374:Progesterone / Q000502:physiology*; D011401:Promoter Regions, Genetic; D044022:Receptor, Endothelin A / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D017422:Sequence Analysis, DNA; D015854:Up-Regulation
chemical_list: D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D044022:Receptor, Endothelin A; D011374:Progesterone