ACTH modulation of transcription factors responsible for steroid hydroxylase gene expression in the adrenal cortex

Abstract

Steroid hormone biosynthesis in the adrenal cortex and gonads involves the coordinated transcription of the genes encoding the steroid hydroxylases, 3beta-hydroxysteroid dehydrogenase (3betaHSD), the steroidogenic acute regulatory protein (StAR), and adrenodoxin (Adx). Transcriptional regulation of steroidogenic genes is multifactorial, entailing developmental, tissue-specific, constitutive, and cAMP-dependent mechanisms. Optimal steroidogenic capacity is achieved by the actions of ACTH which exerts transcriptional pressure on all steroidogenic genes. The actions of ACTH in the adrenal cortex have been studied in great detail and is mediated by cAMP and protein kinase A (PKA) via two temporally distinct pathways. The acute response leads to mobilization of cholesterol, the initial substrate for all steroidogenic pathways, from cellular stores to the inner mitochondrial membrane where cholesterol sidechain cleavage cytochrome P450 (P45011A1) resides. The slower, chronic response of ACTH in the adrenal cortex directs transcription of the genes encoding the steroidogenic enzymes. Although steroidogenic gene transcription in response to ACTH is cAMP-dependent, the consensus cAMP response pathway (CRE/CREB) is not involved. Instead, each steroidogenic gene utilizes unique cAMP-responsive sequences (CRS) found in the promoters of each gene, which bind a diverse array of transcription factors. Moreover, once specific transcription factors are bound to the promoters of the steroidogenic genes, increased gene expression requires posttranslational modification (phosphorylation/dephosphorylation) of the transcription factors and binding of coactivator proteins. This review provides a general view (with emphasis on the human) of the important factors involved in regulating steroidogenic gene expression and ultimately steroid hormone biosynthesis.