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(672) MOLECULAR MECHANISMS OF DEXAMETHASONE-INDUCED REPRESSION OF STEROIDOGENESIS IN MOUSE ADRENOCORTICAL Y-1 TUMOR CELLS. Li, Pihsueh1, Fon, Weiping1, Yang, Jyuerger2, 1 National Cheng Kung University Medical College, Tainan, Taiwan, Republic of China2 National Cheng Kung University Medical College, Tainan, Taiwan, Republic of China ABSTRACT- Evidence from studies in vivo and in vitro suggests that the adrenal cortex is capable of self-suppression. The direct actions of glucocorticoids on the corticosteroid producing cells of the adrenal gland may contribute to the adrenal suppression seen with therapeutic glucocorticoid administration. The steroidogenic acute regulatory protein (StAR) is thought to mediate the rapid increase in steroid hormone biosynthesis by facilitating cholesterol transport to the inner mitochondrial membrane. Tropic hormones trigger upregulation of StAR gene expression by cAMP signaling. Gene transcription is regulated by acetylation and deacetylation of histones. Acetylation of histone H3 is associated with 8-bromo-cAMP-stimulated StAR gene transcription. To ascertain whether the suppressive effect of glucocorticoids on corticosteroidogenesis results from direct glucocorticoid inhibition of StAR gene expression, we investigated the effect of dexamethasone (DEX) on StAR mRNA levels in mouse adrenocortical Y-1 tumor cells. Whether StAR promoter-associated histone H3 acetylation is affected by DEX was then tested Treatment of Y-1 cells with increasing concentrations (0.001 to 10 ug/ml) of DEX for 24 h suppressed 8-bromo-cAMP (0.5 mM)-stimulated StAR protein and mRNA levels and progesterone production in a dose-dependent manner. Treatment of Y1 cells with 8-bromo-cAMP (0.5 mM) for 1-24 h resulted in a marked increase in StAR protein and mRNA levels. This increase was associated with an increase in progesterone production. DEX (10 ug/ml) reduced 8-bromo-cAMP-stimulated StAR protein and mRNA levels. Using chromatin immunoprecipitation assays to assess histone H3 acetylation associated with the StAR promoter, we show that DEX decreased histone H3 acetylation over a 1.3 kb region of the StAR promoter. These results demonstrate that the self-suppressive effect of glucocorticoids on corticosteroidogenesis is at least partly mediated by a decrease in StAR protein and mRNA levels. The mechanism of glucocorticoid action in suppressing StAR gene expression in Y-1 cells involves DNA acetylation. KEY WORDS: StAR, DEXAMETHASONE, ADRENOCORTICAL Y-1 CELLS, ACETYLATION |
