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Glial Cell Missing 1 Regulates Placental Growth Factor (PGF) Gene Transcription in Human Trophoblast¹

Department of Medical Microbiology, Immunology and Cell Biology, and Department of Obstetrics and Gynecology,⁴ Southern Illinois University School of Medicine, Springfield, Illinois 62794 College of Pharmacy and Health Sciences,⁵ Drake University, Des Moines, Iowa 50311

ABSTRACT

Placental growth factor (PGF, previously known as PlGF) is prominently expressed by trophoblasts in human placenta, whereas most nontrophoblast cells express low levels of PGF mRNA under normal physiological conditions. We have shown that hypoxia decreases PGF expression in the trophoblast, but little is known about transcriptional regulation of PGF gene expression. We sought to determine promoter regions of the human PGF gene that contribute to its restricted high constitutive expression in the trophoblast. Overlapping putative promoter regions of human PGF gene encompassing 2–1.5 kb were cloned into reporter vectors and co-transfected into trophoblast and nontrophoblast cell lines. Promoter activity generated by a 2–1.5-kb clone was significantly higher in trophoblasts than in nontrophoblasts. Selective deletion mutants showed that a clone encompassing the PGF (2–828/++34) region generated promoter activity similar to the 2–1.5-kb region in the trophoblast. However, deletion of another 131 bp from this subclone (2–698/++34) resulted in significantly less promoter activity in the trophoblast. The (2–828/2–698) region significantly enhanced activity of a minimal promoter construct in trophoblast but not in nontrophoblast cells, suggesting that this region contributes to regulating PGF transcription in the trophoblast. Site-directed mutagenesis of a glial cell missing 1 (GCM1) motif in the 131-bp region significantly decreased enhancer activity in the trophoblast. Furthermore, overexpression of GCM1 significantly increased PGF 2–1.5-kb promoter activity and PGF mRNA expression in trophoblast and nontrophoblast cells. Forced overexpression of GCM1 restored PGF expression in the hypoxic trophoblast. These data support a functional role for GCM1 contributing to constitutively high trophoblast PGF expression and is the first direct evidence of an oxygen-responsive, trophoblast-specific transcription factor contributing to the regulation of PGF expression.

gene regulation, growth factors, oxygen tension, placenta, placenta growth factor, placental growth factor, PlGF, pregnancy, transcription, trophoblast

¹Supported in part by NIH 5RO1HD36830, HL72802, and an Excellence in Academic Medicine Award from Southern Illinois University School of Medicine.

Correspondence: ²Donald S. Torry, Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, P.O. Box 19626, Springfield, IL 62794-9626. FAX: 217 545 3227; e-mail: dtorry{at}siumed.edu

³These authors contributed equally to this work.

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