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AP-2 (Activating Protein 2) and Sp1 (Selective Promoter Factor 1) Regulatory Elements Play Distinct Roles in the Control of Basal Activity and Cyclic Adenosine 3',5'-Monophosphate Responsiveness of the Human Chorionic Gonadotropin-ß Promoter

Division of Endocrinology, Metabolism and Molecular Medicine Northwestern University Medical School Chicago, Illinois 60611

The CG ß-subunit gene (CGß) arose evolutionarily from the LH ß-subunit gene (LHß) through gene duplication. Although the promoter sequences of the CGß and human (h) hLHß genes are greater than 90% homologous, their expression patterns are distinct. LHß is expressed in pituitary gonadotrope cells and CGß is expressed in placental trophoblast cells. The placental specific and cAMP-inducible region within the CGß promoter has been mapped to a complex enhancer element spanning 118 bp (-318 to -200). Transcription factor-binding sites within this enhancer have been partially characterized and include multiple binding sites for AP-2 (activating protein 2) and Sp1 (selective promoter factor 1), which activate basal and cAMP-induced expression. In this study, we performed a detailed analysis of the recognition sites for these transcription factors and examined the functional roles of these elements in the control of CGß expression. An upstream Sp1/AP-2 binding site (-318 to -279) preferentially binds Sp1, which occludes AP-2 binding to an adjacent site. In contrast, both Sp1 and AP-2 bind concurrently to a downstream composite Sp1/AP-2 element (-220 to -188). Functionally, mutations in any of the Sp1 or AP-2 binding sites cause a progressive decrease in basal CGß expression. However, cAMP stimulation of the CGß promoter is reduced by AP-2 mutations, whereas Sp1 mutations enhance cAMP activation. We conclude that multiple AP-2 and Sp1 elements are required to maintain basal CGß promoter activity, but these factors have opposing effects on cAMP regulation, which is mediated primarily by AP-2.

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