Repression of glycoprotein hormone alpha-subunit gene expression and secretion by activin in alpha T3-1 cells

Molecular Endocrinology
B AttardiG Little

Abstract

The alpha T3-1 cell line, a GnRH-responsive gonadotroph cell line developed by targeted oncogenesis in transgenic mice, was used to study regulation of the glycoprotein hormone alpha-subunit by activin. Transient transfection assays established that activin suppressed transcription of both the human and mouse alpha-subunit genes. Initial studies demonstrated that activin decreased transcription of -846 and -180 human alpha-subunit-luciferase constructs by about 30%, but that inhibin and follistatin were without effect. Subsequent studies to localize sequences mediating responses to activin were carried out using a series of 5'-deletions (-507 to -133) of the mouse alpha-subunit promoter fused to luciferase. The luciferase activity of the -507-base pair construct was decreased by 60-70% in the presence of activin, and follistatin prevented this decrease. There were significant stepwise losses of activin responsiveness when sequences between -507 and -424, -424, and -288, and -288 and -205 base pairs were eliminated. Clustered point mutations of the mouse alpha-subunit gene, shown previously to reduce basal expression and GnRH responsiveness, were tested to further identify sequences mediating activin repression. Constructs conta...Continue Reading

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