Vol 56, No 3 (2005)
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Published online: 2006-03-24

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Regulation of CYP17 gene expression in adrenocortical cells by transforming growth factor-β

Tomasz Lehmann, Justyna Biernacka-Łukanty, Wiesław H. Trzeciak
Endokrynol Pol 2005;56(3):355-355.

Abstract

In the adrenal cortex, CYP genes encoding cytochromes P450 components of steroid hydroxylases are regulated by hormones and growth factors. Cytochrome P450c17, constituent of 17α-hydroxylase/17,20-lyase enzyme complex, essential for production of adrenal androgens, is encoded by CYP17 and the expression of this gene, both basal and ACTH-induced, requires steroidogenic factor-1 (SF-1).
Our studies conducted in human adrenocortical NCI-H295R cells indicated that TGF-β acting through the Smad protein pathway, inhibited both basal and cAMP-stimulated transcription of CYP17, and that the –483/-433 fragment of CYP17 promoter, which contains a putative Sp1 response element, is the target for the inhibitory action of TGF-β.
To elucidate the mechanism of inhibition of CYP17 transcription by TGF-β, the expression of SF-1 was also investigated. It was demonstrated that adenylyl cyclase activator, forskolin which mimicks the effect of ACTH, increased, while TGF-β decreased the level of SF-1 transcript. The maximal decrease of basal SF-1 mRNA level was observed after 48 h of incubation of the cells with TGF-β (60% inhibition), while in forskolin-treated cells TGF-β caused 50% decrease in Sf-1 transcript level, already after 6 h of treatment. In both cases the effect was transcriptional and was accompanied by parallel changes in the level of the protein product of the gene.
It is concluded that CYP17 expression is negatively regulated by TGF-β at the transcriptional level via Smad protein pathway, and that this effect requires the –483/-433 fragment of CYP17 promoter containing a putative Sp1 response element. The effect of TGF-β on the expression of CYP17 is specific, since under the same conditions the expression of CYP11A1 is unaffected, and could be, at least in part, due to the inhibition of SF-1 transcription.

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