Nucleic Acids Research Advance Access published online on June 27, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn416
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Molecular Biology |
A new APE1/Ref-1-dependent pathway leading to reduction of NF-
B and AP-1, and activation of their DNA-binding activity
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Yokohama 226-8501, Japan
*To whom correspondence should be addressed. Tel: +81 45 924 5872; Fax: +81 45 924 5834; Email: handa.h.aa{at}m.titech.ac.jp
Received January 3, 2008. Accepted June 16, 2008.
APE1/Ref-1 is thought to be a multifunctional protein involved in reduction–oxidation (redox) regulation and base excision DNA repair, and is required for early embryonic development in mice. APE1/Ref-1 has redox activity and AP endonuclease activity, and is able to enhance DNA-binding activity of several transcription factors, including NF-
B, AP-1 and p53, through reduction of their critical cysteine residues. However, it remains elusive exactly how APE1/Ref-1 carries out its essential functions in vivo. Here, we show that APE1/Ref-1 not only reduces target transcription factors directly but also facilitates their reduction by other reducing molecules such as glutathione or thioredoxin. The new activity of APE1/Ref-1, termed redox chaperone activity, is exerted at concentration significantly lower than that required for its redox activity and is neither dependent on its redox activity nor on its AP endonuclease activity. We also show evidence that redox chaperone activity of APE1/Ref-1 is critical to NF-B-mediated gene expression in human cells and is mediated through its physical association with target transcription factors. Thus, APE1/Ref-1 may play multiple roles in an antioxidative stress response pathway through its different biochemical activities. These findings also provide new insight into the mechanism of intracellular redox regulation.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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