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J. Biol. Chem., Vol. 279, Issue 50, 52493-52499, December 10, 2004

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Germ Cell Nuclear Factor Relieves cAMP-response Element Modulator -mediated Activation of the Testis-specific Promoter of Human Mitochondrial Glycerol-3-phosphate Dehydrogenase^*

Mirjana Rajkovi, Ralf Middendorff¶||, Marianne G. Wetzel, Danijel Frkovi, Sebastian Damerow, Hans J. Seitz, and Joachim M. Weitzel**

From the Institut für Biochemie und Molekularbiologie and ^¶Institut für Anatomie, Zentrum für Experimentelle Medizin, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany, Institute of Biochemistry, Faculty of Medicine, 11000 Belgrade, Serbia and Montenegro, and ^||Institut für Anatomie und Zellbiologie, Justus-Liebig-Universität Giessen, 35385 Giessen, Germany

Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is an essential component of the glycerol phosphate shuttle that transfers reduction equivalents from the cytosol into the mitochondrion. Within the testis, immunohistological analysis localized human mGPDH to late spermatids and to the midpiece of spermatozoa. The expression of human mGPDH is regulated by two somatic promoters, and here, we describe a third testis-specific promoter of human mGPDH. The usage of this testis-specific promoter correlates with the expression of a shortened mGPDH transcript of 2.4 kb in length, which is solely detectable from testicular RNA. Within the testis-specific promoter, we detected a cAMP-response element (CRE) site at -51, which binds the testis-specific transcriptional activator CRE modulator (CREM) in electrophoretic mobility shift assays. This recognition site overlaps with a nuclear receptor binding half-site at -49, which binds the testis-specific transcriptional repressor germ cell nuclear factor (GCNF). Both factors compete for binding to the same DNA response element. Ectopic expression of CREM in HepG2 cells activated a promoter-driven luciferase construct in transient transfection experiments. Additional cotransfection of GCNF relieved this activity, suggesting a down-regulation of CREM-mediated activation by GCNF. This effect was preserved by introducing the CRE/nuclear receptor-binding element into a heterologous promoter context. Our data suggest a down-regulation of CREM-mediated gene expression by GCNF, which might be a general regulation mechanism for several postmeiotically expressed genes with a temporal expression peak during early spermatid development.

Received for publication, April 22, 2004 , and in revised form, August 30, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AC092686 and AF311325.

^* This work was supported by grants from the Deutsche Forschungs-gemeinschaft (GRK336 and WE2458/3-1) (to R. M., H. J. S., and J. M. W.). 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.

^** To whom correspondence should be addressed: Institut für Biochemie und Molekularbiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Tel.: 49-40-42803-4526; Fax: 49-40-42803-4862; E-mail: weitzel{at}uke.uni-hamburg.de.

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