Oxidation of zinc finger transcription factors: physiological consequences.
Redox-sensitive cysteine residues are present in the interaction domains of many protein complexes. There are examples in all of the major categories of transcription factors, including basic region, leucine zipper, helix-loop-helix, and zinc finger. Zinc finger structures require at least two zinc-coordinated cysteine sulfhydryl groups, and oxidation or alkylation of these can eliminate DNA-binding and transcriptional functions. We review here the evidence for oxidation of zinc finger cysteines, the pathways and reactive oxygen intermediates involved, and the functional and physiological consequences of these reactions. Despite skepticism that the strongly reducing intracellular environment would permit significant oxidation of cysteine residues within zinc finger transcription factors, there is compelling evidence that oxidation occurs both in vitro and in vivo. Early reports demonstrating reversible oxidation of zinc-coordinated cysteines with loss of binding function in vitro were shown to reflect accurately the changes in intact cells, and these in turn have been shown to correlate with physiological changes. In particular, the accumulation of oxidized Spl zinc fingers during aging, and estrogen receptors in tamoxifen-resistant breast cancers are dramatic examples of what may be a general sensitivity of zinc finger factors to changes in the redox state of the cell.
Webster
K A
KA
Department of Molecular and Cellular Pharmacology, University of Miami Medical Center, FL 33136, USA. kwebster@chroma.med.miami.edu
Prentice
H
H
Bishopric
N H
NH
D000375:Aging / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D051766:Early Growth Response Protein 1; D029968:Escherichia coli Proteins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013439:Sulfhydryl Reagents / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D016335:Zinc Fingers / Q000502:physiology*
D000975:Antioxidants; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D029968:Escherichia coli Proteins; D017874:Immediate-Early Proteins; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D016329:Sp1 Transcription Factor; D013439:Sulfhydryl Reagents; D014157:Transcription Factors; D013481:Superoxides; D004247:DNA; D010088:Oxidoreductases; D003545:Cysteine