Inhibition of the DNA‐binding activity of NF‐κB by gold compounds in vitro

Yang, Jian; Merin, Jocelyn P.; Nakano, Tatsunori; Kato, Takuma; Kitade, Yukio; Okamoto, Takashi

doi:10.1016/0014-5793(95)00157-5

Cited by 149 publications

(94 citation statements)

References 17 publications

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“…The inhibitory effect of auranofin appeared by reducing mRNA level of these cytokines, suggesting that it blocks some common step in the signal pathways for the transcriptional activation of IL-1 and TNF genes (30). In conjunction with these results, various metal compounds, including gold thiolates, were shown to inhibit the in vitro binding of NF-B to DNA, albeit only in relatively high concentrations (31).…”

mentioning

confidence: 80%

Thiol-Reactive Metal Compounds Inhibit NF-κB Activation by Blocking IκB Kinase

Jeon

Jeong

Jue

2000

The Journal of Immunology

214

174

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Gold compounds are used in the treatment of rheumatoid arthritis. NF-κB is a transcription factor implicated in the expression of many inflammatory genes. NF-κB is activated by signal-induced phosphorylation and subsequent degradation of inhibitory IκB (inhibitory protein that dissociates from NF-κB) proteins, and a multisubunit IκB kinase (IKK) has been identified previously. We tested the effect of various gold compounds on the activation of NF-κB and IKK in LPS-stimulated RAW 264.7 mouse macrophages. A lipophilic gold compound, auranofin, suppressed the LPS-induced increase of nuclear κB-binding activity, degradation of IκB proteins, and IKK activation. Auranofin also blocked IKK activation induced by TNF and PMA/ionomycin, suggesting that the target of auranofin action is common among these diverse signal pathways. In vitro IKK activity was suppressed by addition of hydrophilic gold compounds, such as aurothiomalate, aurothioglucose, and AuCl3. Other thiol-reactive metal ions such as zinc and copper also inhibited IKK activity in vitro, and induction of IKK in LPS-stimulated macrophages. In vitro IKK activity required the presence of reducing agent and was blocked by addition of thiol group-reactive agents. Two catalytic subunits of IKK complex, IKKα and IKKβ, were both inhibited by these thiol-modifying agents, suggesting the presence of a cysteine sulfhydryl group in these subunits, which is critical for enzyme activity. The antiinflammatory activity of gold compounds in the treatment of rheumatoid arthritis may depend on modification of this thiol group by gold.

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confidence: 80%

Thiol-Reactive Metal Compounds Inhibit NF-κB Activation by Blocking IκB Kinase

Jeon

Jeong

Jue

2000

The Journal of Immunology

214

174

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“…Alternatively, under certain circumstances, antioxidants may directly inhibit IKK kinase activity or NF-kB DNA-binding by affecting the redox state of critical Cys residues in the IKK kinase activation loop and NF-kB DNA-binding loop (Gloire et al, 2006;Bubici et al, 2006). For example, the oxidation state of NF-kB seems important for its interaction with DNA (Yang et al, 1995), and its DNA binding can be blocked by interaction with thiol-reactive metals (Shumilla et al, 1998).…”

Section: Antioxidantsmentioning

confidence: 99%

Inhibitors of NF-κB signaling: 785 and counting

2006

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“…On one hand, anti-oxidants could block the production of ROIs that lead to degradation of IkBa. On the other, DNA binding by NF-kB could be directly regulated by the redox potential of the cell; for example, at least in vitro, the oxidation state of NFkB seems important for its interaction with DNA (Yang et al, 1995), and its DNA binding can be blocked by interaction with thiol reactive metals (Shumilla et al, 1998). Animal models have indicated that the anti-oxidant PDTC may have clinical applications for the treatment of septic shock and certain retinal neovascular diseases, due to the ability of PDTC to block NF-kB induction (Lauzurica et al, 1999;Yoshida et al, 1999).…”

Section: Anti-oxidant Moleculesmentioning

confidence: 99%