title: A new APE1/Ref-1-dependent pathway leading to reduction of NF-kappaB and AP-1, and activation of their DNA-binding activity.
abstract: 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-kappaB, 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-kappaB-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.
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Yokohama 226-8501, Japan.
authors.forename: Kozue
authors.initials: K
authors.lastname: Ando
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirao
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kabe
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ogura
authors.forename: Iwao
authors.initials: I
authors.lastname: Sato
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Wada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Handa
mesh_terms: D000818:Animals; D002460:Cell Line; D003545:Cysteine / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D013879:Thioredoxins / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D018832:Molecular Chaperones; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D013879:Thioredoxins; D004247:DNA; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D005978:Glutathione; D003545:Cysteine