Complex assembly on the human CYP17 promoter

Abstract

Optimal steroid hormone biosynthesis occurs via the integration of multiple regulatory processes, one of which entails a coordinate increase in the transcription of all genes required for steroidogenesis. In the human adrenal cortex adrenocorticotropin (ACTH) activates a signaling cascade that promotes the dynamic assembly of protein complexes on the promoters of steroidogenic genes. For CYP17, multiple transcription factors, including steroidogenic factor-1 (SF-1), GATA-6, and sterol regulatory binding protein 1 (SREBP1), are recruited to the promoter during activated transcription. The ability of these factors to increase CYP17 mRNA expression requires the formation of higher order coregulatory complexes, many of which contain enzymatic activities that post-translationally modify both the transcription factors and histones. We discuss the mechanisms by which transcription factors and coregulatory proteins regulate CYP17 transcription and summarize the role of kinases, phosphatases, acetyltransferases, and histone deacetylases in controlling CYP17 mRNA expression.

Fig. 1

Model for transcriptional regulation of human CYP17. In response to ACTH, PKA activation stimulates multiple proteins, including SK1 (sphingosine kinase 1), DGKθ (diaclyglycerol kinase theta). It is likely that PKA modulates the activity of several other proteins in adrenocortical cells. Activated DGKθ phosphorylates diacylglycerol (DAG) to form phosphatidic acid (PA). Increased nuclear concentrations of PA facilitate dissociation of sphingosine (SPH) and corepressor proteins [Sin3A, histone deacetylase (HDAC), silencing mediator of retinoid and thyroid receptors (SMRT)]. Binding of PA to steroidogenic factor-1 (SF-1) promotes the assembly of a transcription activator complex containing SRC1 (steroid receptor coactivator 1), the histone acetyltransferase GCN5 (general control nonderepressed 5), p54, and polypyrimidine-tract binding protein-associated splicing factor (PSF). PKA also activates SK1, which converts SPH to sphingosine-1-phosphate (S1P). S1P activates the cleavage and nuclear import of sterol regulatory element binding protein 1c (SREBP1c) via a Ca²⁺-dependent pathway. Constitutive CYP17 expression is mediated by a complex containing specificity protein (Sp) 1, Sp3, and nuclear factor 1C (NF1C). Basal transcription is also mediated by GATA-6, which binds to Sp1. In response to cAMP GATA-6 synergizes with SF-1 to activate CYP17 transcription.