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Regular Article |
a Human Molecular Genetics Group, Institut de Génétique Humaine, CNRS UPR1142, 34396 Montpellier Cedex 5, France
ABSTRACT
In mammals, male sex determination is initiated by SRY (sex-determining region of the Y chromosome) gene expression and followed by testicular development. This study describes specific down-regulation of the human SRY gene transcription by cAMP stimulation using reverse transcription-polymerase chain reaction experiments. Using transfection experiments, conserved nuclear hormone receptor (NHR1) and Sp1 consensus binding sites were identified as essential for this cAMP transcriptional response. Steroidogenic factor-1 (SF-1), a component of the sex-determination cascade, binds specifically to the NHR1 site and activates the SRY promoter. Activation of SF-1 was abolished by cAMP pretreatment of the cells, suggesting a possible effect of cAMP on the SF-1 protein itself. Indeed, human SF-1 protein contains at least two in vitro cAMP-dependent protein kinase (PKA) phosphorylation sites, leading after phosphorylation to a modification of both DNA-binding activity and interaction with general transcription factors such as Sp1. Taken together, these data suggest that cAMP responsiveness of human SRY promoter involves both SF-1 and Sp1 sites and could act via PKA phosphorylation of the SF-1 protein itself.
1 Supported by the European Economic Community through BIOMED2 Grant BMH4-CT96-0790 and Ligue Nationale contre le Cancer and Association pour la Recherche sur le Cancer (ARC). P.D.S.B. was supported by a postdoctoral fellowship from ARC (Association pour la Recherche contre le Cancer).
2 Correspondence: Philippe Berta, IGH-CNRS UPR 1142, 141 rue de la Cardonille, 34396 Montpellier Cedex 5, France. FAX: 33 4 99 61 99 01; berta{at}igh.cnrs.fr
3 Current address: Department of Pathology and Pediatric Surgical Research, Massachusetts General Hospital, 32 Fruit St., Boston, MA 02114.
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