SF-1 CONTROLS THE EXPRESSION OF THE SCAVENGER GENE AKR1B7: IN VITRO AND IN VIVO APPROACHES

• Published in: Endocrine research 2002-01, Vol.28 (4), p.515-518
• Main Authors: Martinez, A., Val, P., Jean, C., Veyssière, G., Lefrançois-Martinez, A. M.
• Format: Article
• Language: English
• Subjects: Aldehyde Reductase; Animals; DNA-Binding Proteins - physiology; Fushi Tarazu Transcription Factors; Gene Expression Regulation - physiology; Homeodomain Proteins; Mice; Proteins - genetics; Receptors, Cytoplasmic and Nuclear; Steroidogenic Factor 1; Transcription Factors - physiology
• ISSN: 0743-5800; 1532-4206
• DOI: 10.1081/ERC-120016831

EXPANDED ABSTRACT The akr1b7 mvdp gene (aldo keto reductase 1B7 mouse vas deferens protein) encodes a tissue-specific aldose reductase expressed in the steroidogenic glands of different rodents and in the vas deferens solely in mouse.[1], [2] In the former tissues this enzyme acts as a scavenger of isocaproaldehyde derived from side chain cleavage of cholesterol during the first step of steroidogenesis.[3] Akr1b7 mvdp is ACTH-responsive in the adrenal cortex (ZF) while androgen is the main inducer in the vas deferens.4-6 We have previously established that the −510 +41 akr1-b7 promoter fragment is able to reproduce the endogenous gene zona fasciculata restricted, ACTH controlled expression, in transgenic mice adrenals.[7], [8] Here, we report that three response elements contained within this promoter (positions −102, −458, −503) are able to bind SF-1, the essential regulator of steroidogenesis, although the low affinity site at −503 retains some other specific proteins present in Y1 nuclear extracts. Mutation of the −102 site results in a lowering of the activity of the −510 +41 promoter in Y1 cells, whereas mutation of the −458 site induces a reduction both in the global activity and forskolin sensitivity of the promoter. Interestingly, differential mutations of the −503 site nucleotides either induce an increase or a decrease in the basal and forskolin-induced activity.[9] Then we raised the question of the physiological importance of the atypical SF-1 binding site at position −102 that was previously described to overlap a proximal androgen responsive element (AREp) by in vitro studies.[10], [11] In order to investigate the in vivo requirement for the −102 SFRE AREp for adrenal expression and ACTH regulation, we generated transgenic mice harboring mutant contructs of the 1.8-kb promoter driving the CAT reporter. Adrenal expression in adult mice is impaired in all lines harboring the mutated −102 SFRE AREp. Impaired gene expression in mice harboring the mutated −102 SFRE AREp transgene is linked to impaired SF-1 binding and not to impaired AR binding since we showed that akr1b7 gene expression is not affected in the adrenals of Tfm mice which are naturally defective for AR. Interestingly, requirement for the −102 SFRE AREp varies during development since the mutant and the wild type transgenes share similar expression pattern until postanatal day 15 and differ thereafter. Finally, the −102 SFRE is not essential for hormonal regulation since its mutation