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J. Biol. Chem., Vol. 277, Issue 43, 41259-41267, October 25, 2002
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From the Division of Endocrinology and Diabetology, University
Hospital, CH-111 Geneva 14, Switzerland
Angiotensin II (Ang II) and adrenocorticotropic
hormone stimulate aldosterone biosynthesis in the zona glomerulosa of
the adrenal cortex through induction of the expression of the
steroidogenic acute regulatory (StAR) protein, which promotes
intramitochondrial cholesterol transfer. To understand the mechanism of
this induction of the StAR protein, we have examined the effect
of Ang II and forskolin, a mimicker of adrenocorticotropic hormone
action, on two transcription factors known to modulate StAR
gene expression in opposite ways, DAX-1 and SF-1, in bovine
adrenal glomerulosa cells in primary culture. Ang II markedly inhibited
DAX-1 protein expression in a time- and concentration-dependent
manner (to 38.7 ± 12.9% of controls at 3 nM after
6 h, p < 0.01), an effect that required de
novo protein synthesis and ERK2/1 activation. This effect was
associated with a concomitant decrease in DAX-1 mRNA and an
increase in mitochondrial StAR protein levels. Similarly, forskolin
dramatically repressed DAX-1 protein and mRNA expression (to
19.6 ± 1.8 and 50.3 ± 4.7% of controls, respectively,
p < 0.01). Neither Ang II nor forskolin affected
DAX-1 protein and mRNA stability. The aldosterone response to Ang
II was markedly reduced (to 59 ± 4% of controls,
p < 0.01) in transiently transfected cells
overexpressing DAX-1. Whereas Ang II was without effect on SF-1
expression, forskolin significantly increased SF-1 protein and mRNA
levels in a cycloheximide-sensitive manner (to 167.4 ± 16.6 and
173.1 ± 25.1% of controls after 6 h, respectively, p < 0.01). These results demonstrate that the balance
between repressor and inducer function of DAX-1 and SF-1 are of
critical importance in the regulation of adrenal aldosterone biosynthesis.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF421373.
Repression of DAX-1 and Induction of SF-1 Expression
TWO MECHANISMS CONTRIBUTING TO THE ACTIVATION OF ALDOSTERONE
BIOSYNTHESIS IN ADRENAL GLOMERULOSA CELLS*
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of
Endocrinology and Diabetology, University Hospital, 24, rue
Micheli-du-Crest, CH-111 Geneva 14, Switzerland. Tel.: 41-22-372-93-62;
Fax: 41-22-372-93-29; E-mail:
alessandro.capponi@medecine.unige.ch.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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