Redox Regulation of Ap-1

Abstract

The inducible transcription factor, AP-1, is a heterodimeric leucine zipper complex containing the protein products of thefos and jun protooncogenes. The DNA binding activity of Fos and Jun is regulated in vitro by a posttranslational mechanism involving reduction-oxidation. Redox regulation is mediated through a conserved cysteine residue located in the DNA binding domain of both proteins. Oxidation or chemical modification of the cysteine has an inhibitory effect on AP-1 DNA binding activity. Conversely, reduction of this residue by chemical reducing agents or by a ubiquitous nuclear redox factor (Ref-1), purified and cloned from human cells, stimulates AP-1 DNA binding activity. In addition, recombinant Ref-1 stimulates the DNA binding activity of several other classes of redox regulated transcription factors. Immunodepletion studies indicate that Ref-1 is the major AP-1 redox activity in Hela cells. Interestingly, Ref-1 is a bifunctional protein; it also possesses an apurinic/apyrimidinic (A/P) endonuclease DNA repair activity. However, the redox and DNA repair activities of Ref-1 are physically and biochemically distinguishable. Ref-1 may represent a novel component of the signal transduction processes that regulate eukaryotic gene expression in response to cellular stress.