Thioredoxin reductase regulates AP-1 activity as well as thioredoxin nuclear localization via active cysteines in response to ionizing radiation

Shervin Karimpour, Junyang Lou, Lilie L. Lin, Luis M. Rene, Lucio Lagunas, Xinrong Ma, Sreenivasu Karra, C. Matthew Bradbury, Stephanie Markovina, Prabhat C. Goswami, Douglas R. Spitz, Kiichi Hirota, Dhananjaya V. Kalvakolanu, Junji Yodoi, David Gius

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6317-6327
Number of pages11
JournalOncogene
Volume21
Issue number41
DOIs
StatePublished - 2002

Keywords

  • AP-1
  • Ionizing radiation
  • Redox
  • Thioredoxin
  • Thioredoxin reductase

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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