Novel roles for GATA transcription factors in the regulation of steroidogenesis

Abstract

Steroidogenesis is a tightly regulated process that is dependent on pituitary hormones. In steroidogenic tissues, hormonal stimulation triggers activation of an intracellular signalling pathway that typically involves cAMP production, activation of PKA, and phosphorylation of target transcription factors. In the classic cAMP signalling pathway, phosphorylation of CREB (cAMP response element (CRE)-binding protein) and its subsequent binding to cAMP-response elements (CREs) in the regulatory regions of target genes play a key role in mediating cAMP responsiveness. However, the cAMP responsive regions of several genes expressed in steroidogenic tissues do not contain consensus CREs indicating that other transcription factors are also involved. We have been studying the role played by the GATA family of transcription factors. GATA factors are expressed in a variety of tissues including the adrenals and gonads. Since the regulatory regions of several steroidogenic genes contain GATA elements, we have proposed that GATA factors, particularly GATA-4 and GATA-6, might represent novel downstream effectors of hormonal signalling in steroidogenic tissues. In vitro experiments have revealed that GATA-4 is indeed phosphorylated in steroidogenic cells and that phosphorylation levels are rapidly induced by cAMP. GATA-4 phosphorylation is mediated by PKA. Phosphorylation increases GATA-4 DNA-binding activity and enhances its transcriptional properties on multiple steroidogenic promoters. We now define a new molecular mechanism whereby phospho-GATA factors contribute to increased transcription of steroidogenic genes in response to hormonal stimulation.