Of Signal Transduction

Thioredoxin is induced by a variety of oxidative stress caused by hydrogen peroxide, x-ray- or ultraviolet (UV) -irradiation, viral infection, ischemia-reperfusion, and drugs such as cis-diamminedichloroplatinum (II) and hemin. Hydrogen peroxide induces TRX gene transcription through an oxidative responsive element (18), and hemin induces the gene transcription by regulating NF-E2-related factor (Nrf2) through antioxidant responsive element (ARE) (19).

Thioredoxin translocates from the cytosol to the nucleus upon stress, such as UV, phorbol 12-myristate acetate (PMA), tumor necrosis factor-a (TNF-a), and an anticancer drug (20-22). In the nucleus, TRX enhances DNA binding of transcription factors such as NF-kB, AP-1, and p53 (21-24). Oxidative stress induces activation of NF-kB and antioxidant such as N-acetylcysteine (NAC) suppressed the activation (25). Cytoplasmic TRX suppresses the NF-kB signaling, whereas intranuclear TRX enhances the DNA-binding activity by reducing the key cysteine residue in NF-kB (21). In co-operation with redox factor-1 (Ref-1), TRX enhances the transcriptional activity of p53, "the guardian of genome,'' upregulates p53-dependent p21 expression, and affords cells to repair damaged DNA by inducing cell cycle G1 arrest (22).

Apoptosis signal-regulating kinase 1 (ASK1) was identified by Ichijo et al. (26) as a mitogen-activated protein (MAP) kinase that activates c-Jun N-terminal kinase (JNK) and p38 MAP kinase and induces stress-mediated apoptosis signal. Reduced TRX binds to ASK1 and inhibits the activity of ASK1. Upon oxidative stress, TRX is oxidized and dissociated from ASK1, resulting in the activation of ASK1 (27). In addition, TRX negatively regulates p38 MAP kinase activation (28). Therefore, the cytoprotective effect of TRX can be partly explained by the regulation of the activity of ASK1 or p38 MAP kinase.

The activity of several intracellular enzymes is regulated by TRX. Tumor suppressor PTEN, which is a protein tyrosine phosphatase and reverses the action of phosphoinositide 3-kinase, is inactivated by hydrogen peroxide, and oxidized PTEN is reduced and reactivated by TRX (29). The activity of caspase-3, an apoptosis inducer, is regulated by TRX-mediated redox state. Thioredoxin recovered the activity of caspase-3 that is inactivated by thiol-oxidant (30), suggesting that TRX shifts the cell death mode from necrosis to apoptosis induced by oxidative stress (3).

Thioredoxin-binding proteins (TBPs) were reported in addition to ASK1. We identified TBP-1 as p40phox, a phagocyte oxidase component, and TBP-2 as vitamin D3 upregulated protein 1 (VDUP1), using the yeast two-hybrid system (31,32). Intriguingly, TBP-2/VDUP1 negatively regulates the reducing activity of TRX (31). The expression of TBP-2/ VDUP1 is downregulated in cancer by histone deacetylation, and an inhibitor of histone deacetylase caused cell cycle arrest (33). We recently reported that TBP-2/VDUP1 is correlated with interleukin (IL)-2 dependent growth in HTLV-I infected cell lines and that TBP-2 induces cell cycle G1 arrest by increasing p16 expression (34). The mutation of TBP-2/VDUP1 gene causes hyperlipidemia (35), although it needs to be clarified whether affected TRX-mediated cellular redox is involved in the onset of the disease.

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