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J. Biol. Chem., Vol. 279, Issue 23, 23953-23960, June 4, 2004

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Casein Kinase II-mediated Phosphorylation of NF-B p65 Subunit Enhances Inducible Nitric-oxide Synthase Gene Transcription in Vivo^*

Aurélie Chantôme, Alena Pance, Nolwenn Gauthier, David Vandroux¶, Julie Chenu, Eric Solary, Jean-François Jeannin, and Sylvie Reveneau||

From the Cancer Immunotherapy Laboratory, Ecole Pratique des Hautes Etudes, INSERM U517, and the ^¶Laboratoire de Physiopathologie et Pharmacologie Cardiovasculaires Expérimentalas, Institut Fédératif de Recherche IFR100, Faculty of Medicine, 7, boulevard Jeanne d'Arc, BP 87900, 21079 Dijon, France

Nitric oxide (NO) produced by inducible nitric-oxide synthase (NOSII) is mainly regulated at the transcriptional level by the nuclear factor-B (NF-B). In the present study, we further analyzed the role of NF-B in the in vivo transcriptional regulation of NOSII gene by comparing two clones isolated from the EMT-6 mouse mammary cancer cell line. In response to interleukin (IL)-1 or lipopolysaccharide (LPS), EMT-6 clone J (EMT-6J) cells produce 3-fold more NO than EMT-6 clone H (EMT-6H) cells, an effect correlated with enhanced activation of NF-B in EMT-6J cells. In response to IL-1, the kinetics of degradation of NF-B inhibitors IB- and IB-, the nucleo-cytoplasmic shuttling of the transcription factor and its binding to a specific DNA sequence were similar in both clones. In contrast, an IL-1-induced phosphorylation of serine residues in NF-B p65 subunit was observed in EMT-6J, but not in EMT-6H, cells. This IL-1-induced phosphorylation of p65 was specifically prevented by pretreatment of EMT-6J cells with the casein kinase II inhibitor DRB. Small interfering RNA-mediated depletion of casein kinase II- subunit also decreased NF-B transcriptional activity and NOSII gene transcription in IL-1 and LPS-stimulated EMT-6J cells to the levels observed in EMT-6H cells treated in the same conditions. Altogether, these data indicate that casein kinase II-mediated phosphorylation of p65 subunit can enhance the transcriptional activity of NF-B in vivo. This post-translational modification of the transcription factor can be responsible for increased NOSII gene transcription and NO production in tumor cells exposed to either IL-1 or LPS.

Received for publication, December 16, 2003 , and in revised form, March 16, 2004.

^* This work was supported by the Comité Départemental de la Ligue contre le Cancer de Haute Marne et de la Côte d'Or, the Conseil Régional de Bourgogne, and the Fondation pour la Recherche Médicale (to A. C.). 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.

Current address: Dept. of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.

^|| To whom correspondence should be addressed: EPHE, INSERM U517, Faculty of Medicine, 7, boulevard Jeanne d'Arc, BP 87900, 21079 Dijon, France. Tel.: 33-3-80-39-34-19; Fax: 33-3-80-65-39-30; E-mail: sylvie.reveneau{at}u-bourgogne.fr.

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