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Endocrinology Vol. 138, No. 6 2621-2631
Copyright © 1997 by The Endocrine Society

ARTICLES

Two Proximal Activating Protein-1-Binding Sites Are Sufficient to Stimulate Transcription of the Ovine Follicle-Stimulating Hormone-ß Gene1

Brian D. Strahl, Huey-Jing Huang, Norma R. Pedersen, Joyce C. Wu, Basavdutta R. Ghosh2 and William L. Miller

Department of Biochemistry, North Carolina State University, Raleigh, North Carolina 27695-7622

Address all correspondence and requests for reprints to: Dr. William L. Miller, Department of Biochemistry, Box 7622, North Carolina State University, Raleigh, North Carolina 27695-7622.

FSH is an important regulator of mammalian gametogenesis and the female reproductive cycle. Although little is known about the transcriptional regulation of the ß-subunit (the rate-limiting subunit of FSH synthesis), sequence analysis of the ovine FSHß promoter has revealed a number of potential activating protein-1 (AP-1; Jun/Fos)-binding sites. To determine whether the gene encoding the ß-subunit of ovine FSH (oFSHß) is responsive to AP-1 transcriptional complexes, chimeric constructs containing deleted portions of the oFSHß promoter fused to a luciferase reporter were transiently transfected along with c-Jun and c-Fos expression constructs into JAR cells. Analysis of these deletion constructs revealed that the proximal promoter of oFSHß is highly stimulated by c-Jun and c-Fos proteins (typically 20-fold with a reporter construct containing oFSHß sequences from -215 to +759 bp). This stimulation was lost when a similar construct containing sequences from -84 to +759 bp was tested. Transcriptional start site analysis using reverse transcription-PCR verified that the transcriptional initiation of the -215-bp deletion construct, with or without cotransfected c-Jun/c-Fos, was the same as that observed in vivo. Computer analysis of oFSHß sequences from -215 to +1 bp identified four putative AP-1-like elements, located at -155, -120, -83, and -10 bp. Gel retardation experiments using oligonucleotides corresponding to the four putative AP-1-like sites revealed that only -120 and -83 sites in oFSHß bound AP-1 proteins in vitro. Site-directed mutagenesis of the -120 and -83 sites showed that each element was required for stimulation by c-Jun and c-Fos proteins as well as 12-O-tetradecanoyl phorbol-13-acetate in transient transfection assays. Finally, immunocytochemical dual labeling was used to show that more than 75% of all FSHß-containing cells in ovine pituitary sections from cycling ewes contained nuclear c-Jun, JunB, JunD, and Fos proteins. These data, taken together, show that oFSHß transcription can be stimulated by c-Jun and c-Fos proteins via two functionally linked AP-1-like sites in the oFSHß proximal promoter and that these sites are likely to be important regulators of FSH production in vivo.




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