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Papers In Press, published online ahead of print April 27, 2004
J. Biol. Chem, 10.1074/jbc.M313939200
Submitted on December 19, 2003
Revised on April 27, 2004
Accepted on April 27, 2004

Conditional expression of 15-lipoxygenase-1 inhibits the selenoenzyme thioredoxin reductase: Modulation of selenoproteins by lipoxygenase enzymes

Margaret Yu, Philip J. Moos, Pamela Cassidy, Mark Wade, and Frank A. Fitzpatrick

Oncological Sciences, University of Utah, Salt Lake City, Utah 84112-5550

Corresponding Author: frank.fitzpatrick{at}hci.utah.edu

The selenoenzyme thioredoxin reductase regulates redox-sensitive proteins involved in inflammation and carcinogenesis, including ribonucleotide reductase, p53, NFkappa B, and others. Little is known about endogenous cellular factors that modulate thioredoxin reductase activity. Here we report that several metabolites of 15-lipoxygenase-1 inhibit purified thioredoxin reductase in vitro. 15(S)-Hydroperoxy-5, 8, 11-cis -13-trans- eicosatetraenoic acid, a metastable hydroperoxide generated by 15-lipoxygenase-1, and 4-hydroxy-2-nonenal, its non-enzymatic rearrangement product inhibit thioredoxin reductase with IC50 = 13 ± 1.5 mu M and 1 ± 0.2 mu M, respectively. Endogenously generated metabolites of 15-lipoxygenase-1 also inhibit thioredoxin reductase in HEK 293 cells that harbor a 15-LOX-1 gene under the control of an inducible promoter complex. Conditional, highly selective induction of 15-lipoxygenase-1 caused an inhibition of ribonucleotide reductase activity, cell cycle arrest in G1, impairment of anchorage-independent growth, and accumulation of the pro-apoptotic protein BAX. All of these responses are consistent with inhibition of thioredoxin reductase via 15-lipoxygenase-1 overexpression. In contrast, metabolites of 5-lipoxygenase were poor inhibitors of isolated thioredoxin reductase, and the overexpression of 5-lipoxygenase did not inhibit thioredoxin reductase or cause a G1 cell cycle arrest. The influences of 15-lipoxygenase-1 on inflammation, cell growth and survival may be attributable, in part, to inhibition of thioredoxin reductase and several redox-sensitive processes subordinate to thioredoxin reductase.


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