Oxidation of Zinc-Binding Cysteine Residues in Transcription Factor Proteins

Wilcox, Dean E.; Schenk, Austin D.; Feldman, Brian M.; Xu, Yin Feng

doi:10.1089/15230860152542925

Cited by 65 publications

(58 citation statements)

References 82 publications

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“…After treatment with H 2 O 2 , DTT was able to partially (about 50%) restore the DNA complex formation of VDR/RXR (Fig. 2C) (21), or even thiosulfinate (Cys-SO-S-Cys) (52). Among the amino acids present in proteins only cysteines are modified by NO ⅐ (53), while the other reactive species used in this study are able to modify additional amino acids in proteins also, e.g.…”

Section: Discussionmentioning

confidence: 78%

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Comparing Nitrosative Versus Oxidative Stress toward Zinc Finger-dependent Transcription

Kröncke¹,

Klotz

Suschek³

et al. 2002

Journal of Biological Chemistry

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Effects of nitric oxide (NO ⅐ ) on cellular functions are complex and even appear to be contradictory, janus-headed. NO ⅐ may act cytotoxically but may also protect cells from toxic insults (1), it may compromise the cellular redox state but may also act as an antioxidant (2, 3), and it may activate or inhibit signal transduction pathways (4, 5) and gene transcription (6 -9), respectively. Many of these effects can, at least in part, be explained by different NO ⅐ concentrations achieved in the respective microenvironment. Nanomolar concentrations of NO ⅐ , as typically synthesized in a tightly regulated fashion by constitutively expressed nitric oxide synthase (cNOS), 1 serve as a signal molecule activating the soluble guanylate cyclase to produce cGMP, which acts as a second messenger. However, in addition to two cNOS there is also an inducible NOS (iNOS) expressed in a variety of acute or chronic disease states (for reviews see Refs. 10, 11). Originally described as a cytotoxic activated macrophage effector molecule (12) it is now evident that iNOS-derived NO ⅐ exerts a multitude of biological functions. In an apparently unregulated fashion iNOS synthesizes NO ⅐ for hours or even days resulting in micromolar concentrations of NO ⅐ . Under these conditions NO ⅐ may react with oxygen in a reaction mainly depending on the NO ⅐ concentration to yield higher nitrogen oxides (NO x such as N 2 O 3 , etc.), which display a much broader chemical reaction spectrum than NO ⅐ itself (13). A growing body of evidence suggests that NO ⅐ after reaction to NO x helps to orchestrate gene expression, e.g. via posttranslational modifications of transcription factors. A prevalent DNA binding motif of transcription factors is the zinc finger structure with Zn 2ϩ tetrahedrally coordinated between a ␤-hairpin and a short ␣-helix, creating a small, functional and independently folded domain (14). In these zinc fingers cysteine thiols and histidine imidazole nitrogens serve as direct ligands for the zinc ion.We previously found that NO ⅐ S-nitrosates cysteines in metallothionein, mediating the release of Zn 2ϩ from this zincstoring protein (15), induces Zn 2ϩ release within cells (16) and is able to inhibit zinc finger-dependent transcription (17-19). However, zinc fingers can easily be disrupted by cysteine oxidation, e.g. by reactive oxygen species, or by electrophilic attack, e.g. by alkylating compounds (for reviews see Refs. 20,21). The question therefore arises, whether the reaction of NO ⅐ with zinc fingers may have a special role, different from the reaction with other reactive species generated during inflammatory reactions. Such species are superoxide, its dismutation product hydrogen peroxide, the product of its reaction with NO ⅐ , peroxynitrite, or singlet oxygen, as well as peroxyl radicals.To investigate the impact of these species on the zinc finger integrity, we used the transcription factors VDR and RXR as a model system both containing two Cys 4 -type zinc fingers, which bind to specific promoter sequences as the he...

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Section: Discussionmentioning

confidence: 78%

“…by alkylating compounds (for reviews see Refs. 20,21). The question therefore arises, whether the reaction of NO ⅐ with zinc fingers may have a special role, different from the reaction with other reactive species generated during inflammatory reactions.…”

mentioning

confidence: 99%

Comparing Nitrosative Versus Oxidative Stress toward Zinc Finger-dependent Transcription

Kröncke¹,

Klotz

Suschek³

et al. 2002

Journal of Biological Chemistry

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“…10 It is known that oxidation of zinc finger motif by reactive oxygen species can cause zinc release, leading to dysfunction and degradation of zinc finger transcription factors. 29,30 Clinical data from alcoholic patients has shown that the imbalance between cell death and proliferation in the liver correlates inversely with glutathione levels and directly with lipid peroxidation. 19 Our previous report also showed that zinc supplementation 922 Kang et al AJP April 2008, Vol.…”

Section: Discussionmentioning

confidence: 99%

“…11,12,24 -28 Zinc is a critical component in the zinc finger motif of zinc finger transcription factors, and the release of zinc from the zinc finger motif leads to a loss of the DNA binding ability of zinc finger transcription factors. 29,30 Hepatocyte nuclear factor-4␣ (HNF-4␣), a zinc finger protein, is a liver-enriched transcription factor, 31 and has been reported to bind the promoters of more than 1000 genes involved in most aspects of hepatocyte function including cell proliferation. 32 Both human and animal data demonstrate that HNF-4␣ is essential for maintaining liver gene expression and a decrease in HNF-␣ correlates with the severity of liver damage.…”

mentioning

confidence: 99%

Zinc Supplementation Enhances Hepatic Regeneration by Preserving Hepatocyte Nuclear Factor-4α in Mice Subjected to Long-Term Ethanol Administration

Kang

Song

McClain

et al. 2008

The American Journal of Pathology

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Alcoholic liver disease is associated with sustained liver damage and impaired regeneration, as well as significant zinc deficiency. This study was undertaken to examine whether dietary zinc supplementation could improve liver regeneration by increasing the expression of genes involved in hepatic cellular proliferation in a mouse model of alcoholic liver disease. Adult 129S6 mice fed an ethanol-containing liquid diet for 6 months developed alcoholic liver disease as measured by serum alanine transferase activity and histopathological changes. Zinc supplementation to ethanol-exposed mice enhanced liver regeneration as indicated by increased numbers of proliferation cell nuclear antigen (

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“…We propose that a highly oxidized Cys-110 forms a thiolsulfinate with the thiol group of Cys-132 (Fig. 10A) (33).…”

Section: Molecular Interactions Responsible For the Redox Modulation mentioning

confidence: 96%

Zn2+-dependent Redox Switch in the Intracellular T1-T1 Interface of a Kv Channel

Wang

Strang

Pfaffinger

et al. 2007

Journal of Biological Chemistry

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Oxidation of Zinc-Binding Cysteine Residues in Transcription Factor Proteins

Cited by 65 publications

References 82 publications

Comparing Nitrosative Versus Oxidative Stress toward Zinc Finger-dependent Transcription

Comparing Nitrosative Versus Oxidative Stress toward Zinc Finger-dependent Transcription

Zinc Supplementation Enhances Hepatic Regeneration by Preserving Hepatocyte Nuclear Factor-4α in Mice Subjected to Long-Term Ethanol Administration

Zn2+-dependent Redox Switch in the Intracellular T1-T1 Interface of a Kv Channel

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