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Molecular and Cellular Biology, June 2003, p. 4257-4266, Vol. 23, No. 12
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.12.4257-4266.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cysteine 64 of Ref-1 Is Not Essential for Redox Regulation of AP-1 DNA Binding

Jared M. Ordway, Derek Eberhart,{dagger} and Tom Curran*

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Received 2 December 2002/ Returned for modification 13 February 2003/ Accepted 21 March 2003

Ref-1 participates in DNA repair as well as in redox regulation of transcription factor function. The redox function of Ref-1 involves reduction of oxidized cysteine residues within the DNA binding domains of several transcription factors, including Fos and Jun. Reduction of these residues is required for DNA binding, providing a redox-dependent mechanism for regulation of target gene expression. Previous in vitro studies implicated cysteine 65 of human Ref-1 (cysteine 64 of mouse Ref-1) as the redox catalytic site. We analyzed the in vivo role of cysteine 64 in redox regulation of AP-1 activity by introducing a cysteine-to-alanine point mutation into the endogenous mouse Ref-1 gene (ref-1C64A). Unlike Ref-1 null mice, which die very early in embryonic development, homozygous ref-1C64A mice are viable, they survive to normal life expectancy, and they display no overt abnormal phenotype. Although Ref-1 provides the major AP-1-reducing activity in murine cells, ref-1C64A cells retain normal levels of endogenous AP-1 DNA binding activity in vivo as well as normal Fos- and Jun-reducing activity in vitro. These results demonstrate that Ref-1 cysteine 64/65 is not required for redox regulation of AP-1 DNA binding in vivo, and they challenge previous hypotheses regarding the mechanism by which Ref-1 regulates the redox-dependent activity of specific transcription factors.

* Corresponding author. Mailing address: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105. Phone: (901) 495-2255. Fax: (901) 495-2270. E-mail: fos1{at}aol.com.

{dagger} Present address: Lexicon Genetics, Inc., The Woodlands, TX 77381.

Molecular and Cellular Biology, June 2003, p. 4257-4266, Vol. 23, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.12.4257-4266.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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