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Inhibition of CYP17 expression by adrenal androgens and transforming growth factor β in adrenocortical cells.

100%

Biernacka-Łukanty J. M., Lehmann T. P., Trzeciak W. H.

vol. 51

issue 4

907-917

Cytochrome P450c17, encoded by the CYP17 gene, is a component of the 17a-hydroxylase/17,20-lyase enzyme complex essential for production of adrenal glucocorticoids and androgens as well as gonadal androgens. The expression of CYP17 in adrenocortical cells is stimulated by corticotropin (ACTH) via the signal transduction pathway involving cAMP and protein kinase A (PKA). Thus, in addition to glucocorticoids, ACTH stimulates formation of adrenal androgens, which are known to induce transforming growth factor β (TGF-β) secretion. TGF-β in turn inhibits steroid hormone output by attenuating both basal and ACTH-dependent expression of CYP17. The present study revealed that treatment of bovine and human H295R adrenocortical cells with androgens resulted in a decrease in the basal level of CYP17 transcript and cortisol secretion, without affecting forskolin-stimulated levels. We also demonstrated that in H295R cells TGF-β inhibited both basal and forskolin-stimulated accumulation of CYP17 mRNA. Determination of promoter activity, directing luciferase reporter gene expression in H295R cells transfected with deletion fragments of bovine CYP17 promoter, indicated that the -483 to -433 bp fragment of the promoter was necessary for the inhibitory action of TGF-β on CYP17 expression. It is concluded that in bovine and human adrenocortical cells, androgens inhibit basal CYP17 expression probably at the transcriptional level and independently of the effect of TGF-β.

Temporal pattern of the induction of SF-1 gene expression by the signal transduction pathway involving 3',5'-cyclic adenosine monophosphate.

76%

Lehmann T. P., Biernacka-Łukanty J. M., Saraco N., Langlois D., Li J. Y., Trzeciak W. H.

2005

vol. 52

issue 2

485-491

The objective of our study was to investigate the effect of stimulation of the cAMP-dependent pathway on the expression of an orphan nuclear receptor, SF-1/Ad4BP in mouse adrenal tumour, Y-1 cells in culture. We evaluated the temporal pattern of the effects of corticotropin (ACTH) and the adenylyl cyclase activator forskolin on the level of SF-1 mRNA, and compared the time course of induction of SF-1 with that of CYP11A1. Forskolin, corticotropin and 8-Br-cAMP significantly elevated the level of the SF-1 transcript, after 1.5 h of incubation, with a concomitant increase of SF-1 protein level, observed after 6 h. The CYP11A1 transcript increased gradually over the incubation period, and reached the maximal level after 12 to 24 h. The steady-state level of the SF-1 transcript was unaffected by forskolin when the cells were incubated with actinomycin D, indicating that stimulation of the cAMP pathway results in enhanced transcription of the gene. The effect of forskolin was augmented by cycloheximide, suggesting that an inhibitory protein, whose synthesis was inhibited by cycloheximide, could be involved in negative regulation of SF-1 expression. It is concluded that SF-1 expression is positively regulated by the cAMP pathway at the transcriptional level, and can represent the primary event in cAMP-mediated induction of steroid hormone synthesis in Y-1 cells.

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2 Acta Biochimica Polonica

1 2005

1 2004

2 Biernacka-Łukanty J. M.

2 Lehmann T. P.

2 Trzeciak W. H.

1 Langlois D.

1 Li J. Y.

1 Saraco N.

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Inhibition of CYP17 expression by adrenal androgens and transforming growth factor β in adrenocortical cells.

Temporal pattern of the induction of SF-1 gene expression by the signal transduction pathway involving 3',5'-cyclic adenosine monophosphate.