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The Rat Pituitary Promoter of the Neuronal Nitric Oxide Synthase Gene Contains an Sp1-, LIM Homeodomain-Dependent Enhancer and a Distinct Bipartite Gonadotropin-Releasing Hormone-Responsive Region

Signalisation Cellulaire, Régulation de Gènes et Physiologie de l’Axe Gonadotrope, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7079, Physiologie et Physiopathologie, Université Pierre et Marie Curie, 75252 Paris, France

Address all correspondence and requests for reprints to: Dr. Raymond Counis, Unité Mixte de Recherche 7079 Centre National de la Recherche Scientifique, Physiologie et Physiopathologie, Université Pierre et Marie Curie, 4 Place Jussieu, Case 256, 75252 Paris cedex 05, France. E-mail: raymond.counis{at}snv.jussieu.fr.

The neuronal nitric oxide synthase (NOS I) is expressed and hormonally regulated in rat anterior pituitary gonadotropes. In the present study, we investigated the mechanisms that underlie the constitutive and GnRH up-regulated activity of the pituitary exon 1p promoter of the NOS I gene in these cells. Through the use of 5'-deletions and transient transfections in LßT2, a gonadotrope-derived cell line, we delineated a NOS I cell-specific (NCS) enhancer region (-73/-59) that is required for constitutive activity. Independently of the NCS enhancer, GnRH responsiveness is supported by a bipartite regulatory domain referred to as the GnRH response element I and II located between -33/-10 and -4/+4, the latter consisting of a cAMP-like response element. By combining transient transfections, gel shift, and supershift assays, we demonstrate that Sp1 and LIM-homeodomain-related protein bind the NCS enhancer, whereas cAMP response element binding protein and cAMP regulatory element modulator-like factors bind the GnRH response element II motif. We further show that factors involved in GnRH regulation are also implicated in constitutive activity, suggesting intimate links between constitutive and regulated promoter activity. We speculate that specific expression of the NOS I gene in gonadotropes together with its regulation by GnRH is suggestive of a critical participation of NOS I in gonadotrope function.

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