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J. Biol. Chem., Vol. 281, Issue 13, 8545-8558, March 31, 2006

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Stress Activation of Mammary Epithelial Cell Xanthine Oxidoreductase Is Mediated by p38 MAPK and CCAAT/Enhancer-binding Protein-^*

Katherine J. Seymour, Laura E. Roberts, Mehdi A. Fini^¶, Lisa A. Parmley, Tatiana L. Oustitch, and Richard M. Wright^¶1

From the Department of Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom and the Webb-Waring Institute for Cancer, Aging and Antioxidant Research and the ^¶Department of Pulmonary Sciences, School of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262

Xanthine oxidoreductase (XOR) catalyzes the formation of uric acid from xanthine and hypoxanthine and is recognized as a source of reactive oxygen and nitrogen species. Unexpectedly, XOR was found to play an essential role in milk secretion in the differentiating mammary gland, where it is an integral component of the milk fat globule. XOR gene expression in both mammary glands and differentiating mammary epithelial cells in culture is regulated by the lactogenic hormones prolactin and cortisol. Expression in mammary epithelial cells is also regulated by inflammatory cytokines and induced by cycloheximide. Cycloheximide was found to stimulate XOR gene expression in differentiating HC11 mouse mammary epithelial cells. Activation of XOR gene expression by both cycloheximide and inflammatory cytokines suggested that XOR may be regulated by stress-activated protein kinases, the MAPKs. We demonstrate here that XOR was induced in HC11 cells by low dose cycloheximide and that expression was blocked by inhibitors of p38 MAPK. Accumulation of phospho-p38 was stimulated by low dose cycloheximide. Low dose cycloheximide stress promoted phosphorylation and nuclear accumulation of the CCAAT/enhancer-binding protein- (C/EBP) transcription factor, which was blocked by inhibition of p38. Furthermore, C/EBP was found to activate the mouse XOR promoter, and XOR promoter-C/EBP protein complexes were induced by low dose cycloheximide stress. These data demonstrate, for the first time, that mouse mammary epithelial cell XOR is regulated by p38 MAPK. They identify an essential function of the C/EBP transcription factor in mouse XOR expression and suggest a potential role for p38 MAPK activation of C/EBP in mammary epithelial cells.

Received for publication, July 7, 2005 , and in revised form, January 25, 2006.

^* This work was supported in part National Institutes of Health Grants HL52509 and HL45582 and the Robert and Helen Kleberg Foundation. 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 To whom correspondence should be addressed: University of Colorado HSC, Campus Box C-322, 4200 East 9th Ave., Denver, CO 80262. Tel.: 303-315-4593; Fax: 303-315-8541; E-mail: richard.m.wright{at}uchsc.edu.

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