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Submitted on August 21, 2003
Accepted on October 29, 2003
1 UMR CNRS 6547, Physiologie Comparée et Endocrinologie Moléculaire, Université Blaise Pascal, Clermont II, Complexe Universitaire des Cézeaux, 24 avenue des Landais, 63177 AUBIERE CEDEX, FRANCE.
* To whom correspondence should be addressed. E-mail: a-marie.lefrancois-martinez{at}geem.univ-bpclermont.fr.
Akr1-b7 encodes a scavenger enzyme expressed in steroidogenic glands under pituitary control. In the zona fasciculata of the adrenal cortex where its expression is controlled by ACTH, AKR1-B7 detoxifies isocaproaldehyde produced during the first step of steroidogenesis. Three SFREs (SF-1 Responsive Elements) are contained within the -510/+41 promoter region which was previously demonstrated to drive gene expression in transgenic mice adrenal cortex. All these sequences bind at least SF-1 in Y1 adrenocortical cells nuclear extracts and can be activated by overexpression of this factor in HeLa cells. However, the three SFREs show distinct properties regarding akr1-b7 promoter activity in Y1 cells. Whereas the proximal -102 SFRE supports basal promoter activity, the -458 bona fide SFRE is essential for both basal promoter activity and cAMP responsiveness, although it is unresponsive to cAMP when isolated from its promoter context. This suggests that SF-1 is not a cAMP-responsive factor per se. The neighboring SFRE at -503 is a palindromic sequence that binds monomeric and heteromeric SF-1 as well as an adrenal-specific complex. Using MA-10 Leydig cells and Y1-10r9 mutant cells, we provide evidence that its activity in adrenocortical cells, depends on the binding of the adrenal-specific factor, which is required for basal and cAMP-induced promoter activity. Furthermore, the -503 site has intrinsic cAMP sensing ability in Y1 cells, which is correlated with increased adrenal-specific complex binding. Collectively our results suggest that cAMP responsiveness of the akr1-b7 promoter is achieved through cooperation between the adrenal-specific factor bound to the -503 site and SF-1 bound to the -458 site.
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