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GATA-6 Is Expressed in the Human Adrenal and Regulates Transcription of Genes Required for Adrenal Androgen Biosynthesis

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9032

Address all correspondence and requests for reprints to: William E. Rainey, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9032. E-mail: braine{at}mednet.swmed.edu.

Abstract

GATA-6 and GATA-4 are members of a family of transcription factors (GATA 1–6) that share conserved zinc-finger DNA binding domains. Using semiquantitative RT-PCR, we found that the human adrenal expresses mRNA for GATA-6 but not GATA-4. A recent study showed GATA-6 expression in the adrenal reticularis, the source of adrenal androgens. To investigate the role of GATA-6 in regulation of adrenal cell steroidogenesis, luciferase reporter constructs containing the 5'-flanking DNA from steroidogenic acute regulatory protein, cholesterol side-chain cleavage (CYP11A), 17-hydroxylase (CYP17), and dehydroepiandrosterone-sulfotransferase (SULT2A1) were cotransfected with an expression vector containing GATA-6 into adrenal NCI-H295R cells and nonsteroidogenic HEK293 cells. All promoter/reporter constructs were increased by GATA-6 in the adrenal model. However, in the HEK293 cells only SULT2A1 reporter activity was increased by GATA-6. One key difference between H295R and HEK293 cell lines is the differential expression of steroidogenic factor 1 (SF1). Transfection of HEK293 cells with both GATA-6 and SF1 significantly increased transcriptional activation of all reporter constructs above the effect of GATA-6 or SF1 alone. To determine whether the action of GATA-6 required SF1, we transfected HEK293 cells with each promoter construct plus and minus GATA-6, SF1, and/or the orphan nuclear repressor DAX1. DAX1 opposed SF1-activated transcription of many genes and abolished the GATA-6/SF1 ability to increase reporter activity. These results suggest that the adrenal uses GATA-6 to enhance transcription of steroid-metabolizing enzymes needed to produce dehydroepiandrosterone sulfate. Additionally, GATA-6 works in synergy with SF1 to maximally increase expression of enzymes needed to produce adrenal androgens.

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