Oxidation of 2-Cys-peroxiredoxins by arachidonic acid peroxide metabolites of lipoxygenases and cyclooxygenase-2.

Human peroxiredoxins serve dual roles as anti-oxidants and regulators of H(2)O(2)-mediated cell signaling. The functional versatility of peroxiredoxins depends on progressive oxidation of key cysteine residues. The sulfinic or sulfonic forms of peroxiredoxin lose their peroxidase activity, which allows cells to accumulate H(2)O(2) for signaling or pathogenesis in inflammation, cancer, and other disorders. We report that arachidonic acid lipid hydroperoxide metabolites of 5-, 12-, 15-lipoxygenase-1, and cyclooxygenase-2 oxidize the 2-Cys-peroxiredoxins 1, 2, and 3 to their sulfinic and sulfonic forms. When added exogenously to cells, 5-, 12- and 15-hydroperoxy-eicosatetraenoic acids also over-oxidized peroxiredoxins. Our results suggest that lipoxygenases and cyclooxygenases may affect 2-Cys peroxiredoxin signaling, analogous to NADPH oxidases in the "floodgate" model (Wood, Z. A., Poole, L. B, and Karplus P. A. (2003) Science 300, 600-653). Peroxiredoxin-dependent mechanisms may modulate the receptor-dependent actions of autocoids derived from cellular lipoxygenase and cyclooxygenase catalysis.

TGF-beta induces novel Lef-1 splice variants through a Smad-independent signaling pathway.

The lymphoid enhancer-binding factor (Lef-1) transcription factor is best known for the ability to transduce Wnt signals during development and to mediate excessive Wnt signaling in certain types of cancer. We recently identified and characterized a novel Wnt-like effect of transforming growth factor-beta (TGF-beta) on beta-catenin, the binding partner of Lef-1. Therefore, we sought to determine the effect of TGF-beta on expression of the Lef/T-cell-specific transcription factor (TCF) components of the Wnt pathway. We found that TGF-beta markedly induced Lef-1 mRNA expression in cell lines originating from fetal lung (Mv1Lu) and newborn skin (Balb/MK), tissues that normally express Lef-1 during development. Lef-1 induction was temporally related to but independent of TGF-beta-induced G1 cell cycle arrest. Furthermore, the induction of Lef-1 was independent of both new protein synthesis and Smad-mediated signaling. Using TGF-beta-treated Mv1Lu cells, we identified multiple splice forms of Lef-1, including novel variants that lack both exons 2 and 3. We conclude that the induction of Lef-1 has permissive effects on the well-characterized TGF-beta signal that inhibits c-myc expression and induces a G1 arrest.