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J. Biol. Chem., Vol. 280, Issue 6, 4462-4468, February 11, 2005

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Repression of the Human Sex Hormone-binding Globulin Gene in Sertoli Cells by Upstream Stimulatory Transcription Factors^*

David M. Selva, Kevin N. Hogeveen, and Geoffrey L. Hammond

From the Department of Obstetrics & Gynaecology, University of British Columbia and the B. C. Research Institute for Children's and Women's Health, Vancouver, British Columbia V5Z 4H4, Canada

Expression of the sex hormone-binding globulin gene (SHBG) in the liver produces SHBG, which transports sex steroids in the blood. In rodents, the SHBG gene is also expressed in Sertoli cells giving rise to the testicular androgen-binding protein, which is secreted into the seminiferous tubule where it presumably controls testosterone action. Evidence that the SHBG gene functions in this way in the human testis is lacking, and mice containing a human SHBG transgene (shbg4) under the control of its own promoter sequence are characterized by SHBG gene expression in the liver but not in the testis. A potential cis-element, defined as footprint 4 (FP4) within the human SHBG promoter, is absent in SHBG promoters of mammals that produce the testicular androgen-binding protein, and we have produced mice harboring a shbg4 transgene in which FP4 was deleted to evaluate its functional significance. Remarkably, these mice express the modified human SHBG transgene in the testis as well as the liver. Human SHBG transcripts were found within their Sertoli cells, primary cultures of which secrete human SHBG, and this was increased by treatment with follicle-stimulating hormone, retinoic acid, and estradiol but not testosterone. We have also found that the upstream stimulatory factors (USF-1 and USF-2) bind FP4 in vitro by electromobility shift assay of Sertoli cell nuclear extracts and in vivo by chromatin immunoprecipitation assay and conclude that USF transcription factors repress human SHBG transcription in Sertoli cells through an interaction with FP4 within its proximal promoter.

Received for publication, August 20, 2004 , and in revised form, November 29, 2004.

^* This work was supported in part by an operating grant from the Canadian Institutes of Health Research. 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.

The amino acid sequence of this protein can be accessed through NCBI Protein Database under NCBI accession number AY838765.

Recipient of a Canadian Institutes of Health Research graduate studentship.

A Canada Research Chair in reproductive health. To whom correspondence should be addressed: B. C. Research Institute for Children's and Women's Health, 950 West 28th Ave., Vancouver, BC V5Z 4H4, Canada. Tel.: 604-875-2435; Fax: 604-875-2496; E-mail: ghammond{at}cw.bc.ca.

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