Abstract
A recently identified class of signaling factors uses critical cysteine motif(s) that act as redox-sensitive ‘sulfhydryl switches’ to reversibly modulate specific signal transduction cascades regulating downstream proteins with similar redox-sensitive sites. For example, signaling factors such as redox factor-1 (Ref-1) and transcription factors such as the AP-1 complex both contain redox-sensitive cysteine motifs that regulate activity in response to oxidative stress. The mammalian thioredoxin reductase-1 (TR) is an oxidoreductase selenocysteine-containing flavoprotein that also appears to regulate multiple downstream intracellular redox-sensitive proteins. Since ionizing radiation (IR) induces oxidative stress as well as increases AP-1 DNA-binding activity via the activation of Ref-1, the potential roles of TR and thioredoxin (TRX) in the regulation of AP-1 activity in response to IR were investigated. Permanently transfected cell lines that overexpress wild type TR demonstrated constitutive increases in AP-1 DNA-binding activity as well as AP-1-dependent reporter gene expression, relative to vector control cells. In contrast, permanently transfected cell lines expressing a TR gene with the active site cysteine motif deleted were unable to induce AP-1 activity or reporter gene expression in response to IR. Transient genetic overexpression of either the TR wild type or dominant-negative genes demonstrated similar results using a transient assay system. One mechanism through which TR regulates AP-1 activity appears to involve TRX sub-cellular localization, with no change in the total TRX content of the cell. These results identify a novel function of the TR enzyme as a signaling factor in the regulation of AP-1 activity via a cysteine motif located in the protein.
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Acknowledgements
The authors are indebted to Dr Jeffery Russell for the invaluable technical expertise offered at stages throughout this project. D Gius was supported by grants from the National Institute of Health (1 K08 CA72602-01), and the American Cancer Society (ACS-IRG-58-010-43 and ACS RPG-00-292-01-TBE). DR Spitz was supported by NIH R01 HL51469. NIH CA69593 supported P Goswami. DV Kalvakolanu was supported by grants from the National Institute of Health (R01 CA 78282 and CA 71401).
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Karimpour, S., Lou, J., Lin, L. et al. Thioredoxin reductase regulates AP-1 activity as well as thioredoxin nuclear localization via active cysteines in response to ionizing radiation. Oncogene 21, 6317–6327 (2002). https://doi.org/10.1038/sj.onc.1205749
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DOI: https://doi.org/10.1038/sj.onc.1205749
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