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Papers In Press, published online ahead of print January 22, 2001
J. Biol. Chem, 10.1074/jbc.M010100200
Submitted on November 6, 2000
Revised on January 17, 2001
Accepted on January 22, 2001
Medicine, New England Medical Center/Tufts University School of Medicine, Boston, MA 02111
Corresponding Author: phassoun{at}lifespan.org
The enzyme xanthine oxidase (XO) has been implicated in the pathogenesis of several disease processes, such as ischemia-reperfusion injury, because of its ability to generate reactive oxygen species (ROS). The expression of XO and its precursor xanthine dehydrogenase (XDH) is regulated at pre- and posttranslational levels by agents such as lipopolysaccharide (LPS) and hypoxia. Posttranslational modification of the protein, for example through thiol oxidation or proteolysis, has been shown to be important in converting XDH to XO. The possibility of posttranslational modification of XDH/XO through phosphorylation has not been adequately investigated in mammalian cells, and studies have reported conflicting results. The present report demonstrates that XDH/XO is phosphorylated in rat pulmonary microvascular endothelial cells (RPMEC), and that phosphorylation is greatly increased (~ 50 fold) in response to acute hypoxia (4 hours). XDH/XO phosphorylation appears to be mediated, at least in part, by casein kinase II (CK2) and p38 kinase, as inhibitors of these kinases partially prevent XDH/XO phosphorylation. In addition, the results indicate that p38 kinase, a stress-activated kinase, becomes activated in response to hypoxia (~ 4 fold increase after 1 hour of exposure of RPMEC to hypoxia), further supporting a role for this kinase in hypoxia-stimulated XDH/XO phosphorylation. Finally, hypoxia-induced XDH/XO phosphorylation is accompanied by a 2-fold increase in XDH/XO activity, which is prevented by inhibitors of phosphorylation. In summary, this study shows that XDH/XO is phosphorylated in hypoxic RPMEC through a mechanism involving p38 kinase and CK2, and that phosphorylation is necessary for hypoxia-induced enzymatic activation.
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