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.

Sildenafil treatment in vivo stimulates Leydig cell steroidogenesis via the cAMP/cGMP signaling pathway

“…Our results showed enhanced Cyp17a1 expression in Leydig cells isolated from sildenafil-treated rats, while the expression for StAR and Cyp11a1 remained unchanged. At present, it is difficult to explain such selective stimulation, since multiple transcription factors, including SF-1, GATA-6, and sterolregulatory binding protein-1, can be recruited to the promoter during activated Cyp17a1 transcription (34,37). Although expression of mRNA transcripts for StAR protein was not significantly changed, sildenafil treatment increased the level of mature StAR protein, which was further potentiated in hCG-supported steroidogenesis.…”

The AP-1 family member FOS blocks transcriptional activity of the nuclear receptor steroidogenic factor 1

“…Transcriptional regulation of CYP17 is mediated by several transcription factors (Sewer and Jagarlapudi, 2009), including the nuclear receptor SF-1 (Hanley et al, 2001;Sewer et al, 2002;Dammer et al, 2007). An analysis of the human CYP17 promoter revealed the presence of AP-1 sites located in between the SF-1 sites, leading us to hypothesize an interference of AP-1 factors with SF-1-mediated transcription of CYP17.…”

Human Adrenal Cortex: Epigenetics and Postnatal Functional Zonation

“…The absence of a CpG island in the human CYP17A1 [41] and HSD3B2 [42] genes suggests that direct epigenetic regulation of the CYP17A1 and HSD3B2 promoters is not essential. In humans, expression of CYP17A1 is driven by a complex interaction of TFs [43]. Indirect evidence of epigenetic regulation of human CYP17A1 is tied to the induction of the GATA-4 and GATA-6 TFs by the histone methyltransferase inhibitor 5-aza-2′-deoxycytidine (5- aza-dC) in human adrenocortical NCI-H295A cells [44, 45].…”