Role of cysteine residues of p65/NF-κB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential

Garcı́a-Piñeres, Alfonso; Lindenmeyer, Maja T.; Merfort, Irmgard

doi:10.1016/j.lfs.2004.01.024

Cited by 137 publications

(105 citation statements)

References 45 publications

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“…Nitric oxide (NO)-mediated S-nitrosylation can inhibit p50 DNAbinding activity through modification of Cys-62 (Matthews et al, 1996) (Figure 3; Table 3). Indeed, modification of reactive cysteine residues provides a mechanism through which several oxidizing agents, natural products and natural product derivatives can inhibit both IKK and NF-kB subunits (Straus et al, 2000;Kwok et al, 2001;Garcia-Pineres et al, 2004;Park et al, 2005a;Liang et al, 2006c;Na and Surh, 2006). Interestingly, epoxyquinone A inhibits RelA DNAbinding activity through Cys-38 modification, the equivalent of p50 Cys-62 (Liang et al, 2006b).…”

Section: Termination Of the Nf-jb Responsementioning

confidence: 99%

Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway

2006

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Section: Termination Of the Nf-jb Responsementioning

confidence: 99%

Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway

2006

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“…Recently, a computer-based structural comparison of 103 SLs predicted that a methylene-carbonyl substructure is important for SL-based inhibition of RelA at Cys-38 (Wagner et al, 2006). Interestingly, some SLs, including the natural product parthenolide, have been shown to also inhibit IKKb through a reactive Cys residue (Cys-179), which is in the kinase activation loop (Kwok et al, 2001;Garcı´a-Pin˜eres et al, 2004). Thus, the SLs (and some epoxyquinoids; Liang et al, 2006) have multistep inhibitory activity within the NF-kB signaling pathway, targeting both IKK activity and NF-kB subunit DNA binding.…”

Section: Inhibitors Of Nf-kb Dna Bindingmentioning

confidence: 99%

Inhibitors of NF-κB signaling: 785 and counting

2006

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“…PTL has also been reported to induce apoptosis via caspase activation and mitochondrial dysfunction, disruption in intracellular thiols and calcium equilibrium, as well as activation of pro-apoptotic Bcl-2 family members [155,167,168]. PTL is a potent inhibitor of NF-κB activation and has been shown to directly bind to IKK and to inhibit DNA binding by alkylating cysteine residue in p65 subunit [34,77]. In addition, PTL sensitizes cancer cells to other antitumor agents [104,142] and was found to act as a chemopreventive agent in a UVB-induced mouse skin cancer model [157].…”

Section: Pre-clinical and Clinical Trials Of Nf-κb Inhibitorsmentioning

confidence: 99%

NF‐κB as a potential molecular target for cancer therapy

et al. 2007

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Abstract. Nuclear factor κB (NF-κB), a transcription factor, plays an important role in carcinogenesis as well as in the regulation of immune and inflammatory responses. NF-κB induces the expression of diverse target genes that promote cell proliferation, regulate apoptosis, facilitate angiogenesis and stimulate invasion and metastasis. Furthermore, many cancer cells show aberrant or constitutive NF-κB activation which mediates resistance to chemo-and radio-therapy. Therefore, the inhibition of NF-κB activation and its signaling pathway offers a potential cancer therapy strategy. In addition, recent studies have shown that NF-κB can also play a tumor suppressor role in certain settings. In this review, we focus on the role of NF-κB in carcinogenesis and the therapeutic potential of targeting NF-κB in cancer therapy.Keywords: NF-κB, NF-κB inhibitor, carcinogenesis, cancer therapy Structure, function and regulation of NF-κBNuclear factor-κB (NF-κB) was first identified in 1986 as a transcription factor that binds to a 10 bp DNA element in kappa immunoglobulin light-chain enhancer in B cells [128]. The mammalian NF-κB family consists of 5 members: NF-κB1 (p50/p105), NF-κB2 (p52/p100), c-Rel, RelA (p65) and RelB (Fig. 1). RelA, c-Rel and RelB are synthesized in their mature forms and contain a transactivation domain that interacts with the transcriptional apparatus. On the other hand, NF-κB1 (p50/p105) and NF-κB2 (p52/p100) are synthesized in precursor forms (p100 and p105) which contain C-terminal ankyrin repeats that are proteolysed by the proteasome resulting in the production of mature proteins (p50 and p52). Both p50 and p52 contain a DNA binding domain but lack a transactivation domain. NF-κB proteins exist in unstimulated cells as homo-or heterodimers bound to IκB proteins. Whereas RelB forms only heterodimers, all the other proteins can form both homo-and heterodimers. NF-κB proteins are characterized by the presence of a highly conserved 300 amino acid Rel homology domain that is located toward the N terminus of the protein, and which is responsible for DNA binding, dimerization, and interaction with specific inhibitory factors known as IκB proteins [7,36].

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Role of cysteine residues of p65/NF-κB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential

Cited by 137 publications

References 45 publications

Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway

Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway

Inhibitors of NF-κB signaling: 785 and counting

NF‐κB as a potential molecular target for cancer therapy

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