ROLE OF THREE SF-1 BINDING SITES IN THE EXPRESSION OF THE MVDP/AKR1-B7 ISOCAPROALDEHYDE REDUCTASE IN Y1 CELLS

Abstract

Mvdp/akr1-b7 encodes an aldose-reductase-like enzyme expressed in the zona fasciculata of the adrenal cortex, the function of which is essential for the detoxification of the cholesterol side chain cleavage product, isocaproaldehyde. The −510/+41 akr1-b7 promoter fragment is able to reproduce the endogenous gene zona fasciculata restricted, ACTH-controlled expression, in transgenic mice adrenals. 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.