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J. Biol. Chem., Vol. 278, Issue 52, 52504-52510, December 26, 2003

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Glutamine Stimulates Argininosuccinate Synthetase Gene Expression through Cytosolic O-Glycosylation of Sp1 in Caco-2 Cells^*

Carole Brasse-Lagnel, Alain Fairand, Alain Lavoinne, and Annie Husson

From the Groupe Appareil Digestif, Environnement et Nutrition, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides, Université de Rouen, 76183 Rouen cedex, France

Glutamine stimulates the expression of the argininosuccinate synthetase (ASS) gene at both the level of enzyme activity and mRNA in Caco-2 cells. Searching to identify the pathway involved, we observed that (i) the stimulating effect of glutamine was totally mimicked by glucosamine addition, and (ii) its effect but not that of glucosamine was totally blocked by 6-diazo-5-oxo-L-norleucine (DON), an inhibitor of amidotransferases, suggesting that the metabolism of glutamine to glucosamine 6-phosphate was required. Moreover, run-on assays revealed that glucosamine was acting at a transcriptional level. Because three functional GC boxes were identified on the ASS gene promoter (Anderson, G. M., and Freytag, S. O. (1991) Mol. Cell Biol. 11, 1935–1943), the potential involvement of Sp1 family members was studied. Electrophoretic mobility shift assays using either the Sp1 consensus sequence or an appropriate fragment of the ASS promoter sequence as a probe demonstrated that both glutamine and glucosamine increased Sp1 DNA binding. Immunoprecipitation-Western blot experiments demonstrated that both compounds increased O-glycosylation of Sp1 leading to its translocation into nucleus. Again, the effect of glutamine on Sp1 was inhibited by the addition of DON but not of glucosamine. Taken together, the results clearly demonstrate that the metabolism of glutamine through the hexosamine pathway leads to the cytosolic O-glycosylation of Sp1, which, in turn, translocates into nucleus and stimulates the ASS gene transcription. Collectively, the results constitute the first demonstration of a functional relationship between a regulating signal (glutamine), a transcription factor (Sp1), and the transcription of the ASS gene.

Received for publication, June 25, 2003 , and in revised form, October 17, 2003.

^* This work was supported by a François Aupetit fellowship (2002) (to C. B.-L.). 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: Groupe Appareil Digestif, Environnement et Nutrition, ADEN EA 3234, Faculté de Médecine-Pharmacie de Rouen, 22 blvd. Gambetta, 76183 Rouen cedex, France. Tel.: 33-2-35-14-82-40; Fax: 33-2-35-14-82-26; E-mail: annie.husson{at}univ-rouen.fr.

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