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J. Biol. Chem., Vol. 282, Issue 17, 12527-12536, April 27, 2007

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O-Linked N-Acetylglucosaminyltransferase Inhibition Prevents G₂/M Transition in Xenopus laevis Oocytes^*

Vanessa Dehennaut¹, Tony Lefebvre, Chantal Sellier, Yves Leroy, Benjamin Gross^¶, Suzanne Walker^¶, René Cacan, Jean-Claude Michalski, Jean-Pierre Vilain, and Jean-François Bodart²

From the Laboratoire de Régulation des Signaux de Division, EA 4020, Université des Sciences et Technologies de Lille, SN3, IFR147, 59655 Villeneuve d'Ascq, France, the Unité de Glycobiologie Structurale et Fonctionnelle, UMR 8576 du CNRS, IFR147, Bâtiment C9, Cité Scientifique, 59655 Villeneuve d'Ascq, France, and the ^¶Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115

Full-grown Xenopus oocytes are arrested at the prophase of the first meiotic division in a G₂-like state. Progesterone triggers meiotic resumption also called the G₂/M transition. This event is characterized by germinal vesicle breakdown (GVBD) and by a burst in phosphorylation level that reflects activation of M-phase-promoting factor (MPF) and MAPK pathways. Besides phosphorylation and ubiquitin pathways, increasing evidence has suggested that the cytosolic and nucleus-specific O-GlcNAc glycosylation also contributes to cell cycle regulation. To investigate the relationship between O-GlcNAc and cell cycle, Xenopus oocyte, in which most of the M-phase regulators have been discovered, was used. Alloxan, an O-GlcNAc transferase inhibitor, blocked G₂/M transition in a concentration-dependent manner. Alloxan prevented GVBD and both MPF and MAPK activations, either triggered by progesterone or by egg cytoplasm injection. The addition of detoxifying enzymes (SOD and catalase) did not rescue GVBD, indicating that the alloxan effect did not occur through reactive oxygen species production. These results were strengthened by the use of a benzoxazolinone derivative (XI), a new O-GlcNAc transferase inhibitor. Conversely, injection of O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate, an O-GlcNAcase inhibitor, accelerated the maturation process. Glutamine:fructose-6-phosphate amidotransferase inhibitors, azaserine and 6-diazo-5-oxonorleucine, failed to prevent GVBD. Such a strategy appeared to be inefficient; indeed, UDP-GlcNAc assays in mature and immature oocytes revealed a constant pool of the nucleotide sugar. Finally, we observed that cyclin B2, the MPF regulatory subunit, was associated with an unknown O-GlcNAc partner. The present work underlines a crucial role for O-GlcNAc in G₂/M transition and strongly suggests that its function is required for cell cycle regulation.

Received for publication, January 16, 2007 , and in revised form, February 26, 2007.

^* This work was supported in part by the "Centre National de la Recherche Scientifique," the "Association pour la Recherche contre le Cancer," and the "Université des Sciences et Technologie de Lille I." 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.

¹ Recipient of a fellowship from the "Ministère de la Recherche et de l'Enseignement."

² To whom all correspondence should be addressed. Tel.: 32-0436847; Fax: 32-0434038; E-mail: jean-francois.bodart{at}univ-lille1.fr.

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