2002 Fiscal Year Final Research Report Summary
Studies on Induction and Functions of Thioredoxin Reductase in Stress Responses
| Project/Area Number |
13672345
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental pharmacy
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| Research Institution | Kitasato University |
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Principal Investigator |
HARA Shuntaro Kitasato University Assistant Professor, School of Pharmaceutical Sciences, 薬学部, 講師 (50222229)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Thiorecoxin reductase / Transcription factor / Redox / NF-κB / Stress response / Cadmium |
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| Research Abstract |
Thioredoxin reductase (TrxR) is an antioxidant enzyme that has an ability to reduce thioredoxin (Trx). It is indicated that Trx plays an important role in stress responses, but the role of TrxR in the stress responses remains unclear. To date, three TrxR isozymes, TrxR1, TrxR2 and Trx3, have been identified. Among these isozymes, only TrxR1 is induced by various kinds of stresses. In this study, in order to reveal the role of TrxR in stress responses, the mechanism of induction and the functions of TrxR1 were studied as follows:
(1) Regulation of stress-induced TrxR1 expression - Exposure of bovine arterial endothelial cells (BAEC) to TNFα, PMA+A23187, or Cd upregulated the expression of TrxR1 but neither TrxR2 nor TrxR3. First, role of the promoter region in the huma TrxR1 gene was evaluated by the transient transfection of luciferase reporter vectors into BAEC. Both PMA+A23187 and Cd elevated luciferase activity via the region between-646 and 46 bp. On the other hand, TNFα did not affect the luciferase activity, but the mRNA decay experiments using actinomycin D showed that TNFα stabilized TrxR1 mRNA. These results indicate that both transcriptional activation and posttranscriptional mRNA stabilization may contribute to the stress-induced expression of TrxR1, and that the contributive mechanisms may vary with kinds of stresses.
(2) Role of TrxR1 in stress-responsive transcription factor-mediated gene expression - Reporter gene analysis revealed that the overexpression of TrxR1 enhanced AP-1- and NF-κB-dependent gene expression. The catalytic selenocysteine residue of TrxR1, which is essential for reducing Trx, was required for this activation, and aurothiomalate, an inhibitor of TrxR, suppressed this activation. These results suggest that TrxR1 may act as a positive regulator of stress-responsive transcription factors, AP-1 and NF-κB via its ability to reduce Trx.
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Research Products
(2 results)
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[Publications] Sakurai,A., Yuasa,K., Shoji,Y., Himeno,S., Tsujimoto,M., Kunimoto,M., Imura,N., and Hara,S.: "Overexpression of Thioredoxin Reductase 1 Regulates NF-κB Activation"Journal of Cellular Physiology. (in press). (2003)
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