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J. Biol. Chem., Vol. 279, Issue 1, 152-162, January 2, 2004

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A Novel AP-1 Site Is Critical for Maximal Induction of the Follicle-stimulating Hormone Gene by Gonadotropin-releasing Hormone^*

Djurdjica Coss, Suzanne B. R. Jacobs, Cheryl E. Bender, and Pamela L. Mellon¶

From the Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093-0674

Regulation of follicle-stimulating hormone (FSH) synthesis is a central point of convergence for signals controlling reproduction. The FSH subunit is primarily regulated by gonadotropin-releasing hormone (GnRH), gonadal steroids, and activin. Here, we identify elements in the mouse FSH promoter responsible for GnRH-mediated induction utilizing the LT2 cell line that endogenously expresses FSH. The proximal 398 bp of the mouse FSH promoter is sufficient for response to GnRH. This response localizes primarily to an AP-1 half-site (–72/–69) juxtaposed to a CCAAT box, which binds nuclear factor-Y. Both elements are required for AP-1 binding, creating a novel AP-1 site. Multimers of this site confer GnRH induction, and mutation or internal deletion of this site reduces GnRH induction by 35%. The same reduction was achieved using a dominant negative Fos protein. This is the only functional AP-1 site identified in the proximal 398 bp, since its mutation eliminates FSH induction by c-Fos and c-Jun. GnRH regulation of the FSH gene occurs through induction of multiple Fos and Jun isoforms, forming at least four different AP-1 molecules, all of which bind to this site. Mitogen-activated protein kinase activity is required for induction of FSH and JunB protein. Finally, AP-1 interacts with nuclear factor-Y, which occupies its overlapping site in vivo.

Received for publication, May 6, 2003 , and in revised form, September 29, 2003.

^* This research was supported by NICHD, National Institutes of Health (NIH), through cooperative agreement U54 HD12303 as part of the Specialized Cooperative Centers Program in Reproduction Research (to P. L. M.). This work was also supported by NIH Grant R37 HD20377 (to P. L .M.). The DNA Sequencing Shared Resource, University of California San Diego Cancer Center is funded in part by NCI, NIH, Cancer Center Support Grant P30 CA23100. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by NIH National Research Service Award F32 HD41301 and NIH Grant T32 DK07044.

Supported in part by NIH Grant T32 DK07451.

^¶ To whom correspondence and reprint request should be addressed: Dept. of Reproductive Medicine, University of California, San Diego, 2057 Cellular and Molecular Medicine, East, 9500 Gilman Dr., La Jolla, CA 92093-0674. Tel.: 858-534-1312; Fax: 858-534-1438; E-mail: pmellon{at}ucsd.edu.

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