Endocrine Abstracts (2002) 3 P262

A role for nur-77 in the regulation of adrenal steroid production

SN Kelly, TP Smith, SK Cunningham, TJ McKenna & LS Young

Department of Endocrinology, UCD, Dublin, Ireland.

The adrenal cortex produces aldosterone, cortisol and adrenal androgens in response to secretogogues including ACTH, angiotensin II(A-II) and insulin. Differential regulation of adrenal steroids is through the modulation of specific key steroidogenic enzymes. The capacity of the adrenal to produce cortisol is controlled in part by the transcription of 3beta-hydroxysteroiddehydrogenase (3beta HSD) and production of adrenal androgens by 17 hydroxylase/17-20 lyase (CYP17). Protein expression of CYP17 is up-regulated in the presence of A-II and insulin in human adrenal cell line, H-295, whereas A-II alone and in combination with forskolin increases the expression of 3beta HSD. We examined the ability of these secretogoues to signal through the steroid transcription factor SF-1, and looked for a role for the orphan nuclear receptor nur 77 in regulation of these steroid enzymes. Forskolin, A-II and insulin increased the protein expression and nuclear translocation of steroidogenic factor-1 (SF-1). Using electrophoretic mobility shift assays we demonstrated increased binding of SF-1 to its response element in the presence of forskolin, A-II and insulin but not A-II in combination with forskolin. Conversely, increased protein expression of nur 77 and the greatest binding of nur 77 to its response element was seen when cells were stimulated with A-II in combination with forskolin. Insulin had no effect on protein expression or activity of nur 77. Differential regulation of adrenal steroids is through transcriptional regulation of key steroidogenic enzymes. Our data indicates that nur 77 may regulate steroid enzyme genes relevant to cortisol production. This orphan nuclear transcription factor may in part regulate differential cortisol and adrenal androgen production.

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