Identification of a p65 Peptide That Selectively Inhibits NF-κ B Activation Induced by Various Inflammatory Stimuli and Its Role in Down-regulation of NF-κB-mediated Gene Expression and Up-regulation of Apoptosis

Takada, Yasunari; Singh, Sujay; Aggarwal, Bharat B.

doi:10.1074/jbc.m311192200

Cited by 174 publications

(148 citation statements)

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“…Thus, the inhibition of phosphorylated p65 in the nucleus was mainly due to the decrease of nuclear translocation of p65 by treatment with SFN and PEITC in PC-3 C4 cells, and not by the direct inhibition of phosphorylation elicited by SFN and PEITC. Phosphorylation of p65 at serine 529 is known to be required for NF-kB transcriptional activation (Takada et al, 2004b). Since SFN and PEITC could inhibit the basal and UVCinduced NF-kB transcriptional activity, our results suggest that inhibition on NF-kB transcriptional activation by SFN and PEITC is possibly due to the inhibition of nuclear translocation of p65 and consequently phosphorylation of p65 in PC-3 C4 cells.…”

Section: Discussionmentioning

confidence: 50%

“…Recent studies have shown that the p65 subunit is directly phosphorylated by an upstream kinase before activating downstream genes (Catley et al, 2004;Takada et al, 2004b). Based on those results, we tested whether SFN and PEITC could also inhibit the nuclear translocation and phosphorylation Effects of SFN and PEITC on IKKa and IKKb activity.…”

Section: Sfn and Peitc Inhibit The Level Of P65 In The Nucleusmentioning

confidence: 99%

“…Recent studies revealed that the protein-tyrosine kinase Syk could phosphorylate IkBa through tyrosine and activate NF-kB (Fan et al, 2003;Takada et al, 2003). It is still controversial which kinase is responsible for the phosphorylation of p65, but the phosphorylation of p65 at serine 529 is known to be required for NF-kB transcriptional activation (Takada et al, 2004b). NF-kB has been reported to play an important role in several signal transduction pathways involved in various cancers as well as in chronic inflammatory diseases (Rayet and Gelinas, 1999;Bremner and Heinrich, 2002;Aggarwal et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…The most common nuclear factor kappa B (NF-kB) is a heterodimer composed of p65 and p50 (Greten and Karin, 2004;Suh and Rabson, 2004). NF-kB is activated by a wide variety of stimuli such as tumor necrosis factor (TNF)-alpha, interleukin-1 (IL-1), LPS, UV light, and oxidative stress (Jeong et al, 2004;Takada et al, 2004b). In most cell types, NF-kB is present in the cytosol in an inactive form and is associated with its inhibitor proteins, called inhibitor of NF-kB (IkBs).…”

Section: Introductionmentioning

confidence: 99%

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Suppression of NF-κB and NF-κB-regulated gene expression by sulforaphane and PEITC through IκBα, IKK pathway in human prostate cancer PC-3 cells

et al. 2005

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Section: Discussionmentioning

confidence: 50%

Section: Sfn and Peitc Inhibit The Level Of P65 In The Nucleusmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Suppression of NF-κB and NF-κB-regulated gene expression by sulforaphane and PEITC through IκBα, IKK pathway in human prostate cancer PC-3 cells

et al. 2005

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“…(17) have been used to deliver peptides and small proteins to cells by an energy-and receptor-independent mechanism with the aim of interfering in signaling processes. Examples include protein transduction domain peptides directed against STAT3 (18), extracellular signal-regulated kinase (19), and NF-B (20). To analyze the importance of the N terminus of MAST205, we synthesized protein transduction domain MAST205 peptides targeting a high scoring PEST sequence, thought to control proteasomal degradation (21) (residues 218 -233; peptide 1) and a potential TRAF2 binding epitope (residues 188 -201; peptide 2).…”

Section: Traf6-induced Nf-b Activity Ismentioning

confidence: 99%

Interaction of TRAF6 with MAST205 Regulates NF-κB Activation and MAST205 Stability

Xiong

Chen

et al. 2004

Journal of Biological Chemistry

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The binding of immune complexes to macrophage Fc␥ receptor results in a subsequent inhibition of lipopolysaccharide-stimulated interleukin-12 synthesis without affecting the induction of tumor necrosis factor-␣. RNA interference targeting MAST205, a 205-kDa serine/ threonine kinase, and transfection of dominant negative MAST205 mutants also mimic this type II macrophage phenotype. Our previous epistasis experiments suggested that the position of MAST205 in the TLR4 signal pathway was proximal to the I B kinase complex. We now report that MAST205 forms a complex with TRAF6, resulting in the inhibition of TRAF6 NF-B activation. We have identified a peptide (residues 218 -233) from the N terminus of MAST205 that, when coupled to a protein transduction domain, inhibits the lipopolysaccharidestimulated activation of NF-B, modulates the size of the MAST205⅐TRAF6 complex, and inhibits ubiquitination of TRAF6. A dominant negative N-terminal MAST205 deletion mutant also inhibits TRAF6 ubiquitination. The domain required for degradation of MAST205 after Fc␥ receptor activation resides within the N-terminal 261 residues, and degradation is triggered by protein kinase C isoform phosphorylation of Ser/Thr residues. These results suggest that MAST205 functions as a scaffolding protein controlling TRAF6 activity and, therefore, plays an important role in regulating inflammatory responses.MAST205 1 is a 205-kDa Ser/Thr kinase that is widely expressed at low levels and highly expressed in spermatids, where MAST205 associates with microtubules. At neuromuscular synapses MAST205 interacts with ␤-2 syntrophin (1, 2). In addition to a well conserved protein kinase C/A kinase domain, MAST205 has a PDZ domain, a protein-protein recognition module (3). The role of MAST205 in cellular physiology, however, has yet to be determined. We have found that MAST205 plays a central role in the regulation of LPS-induced cytokine responses of macrophages (4). In this paper we analyze in greater detail the position of MAST205 in LPS-induced signal pathways and the factors regulating stability of the protein.Macrophages respond to LPS by secreting proinflammatory cytokines such as tumor necrosis factor-␣, IL-1, IL-6, IL-8, and IL-12. IL-12, in particular, is required for the induction of a T helper 1 response that facilitates the clearance of intracellular pathogens. The signal cascade leading to the inflammatory response is complex, reflecting both the importance of controlling the synthesis of potentially harmful cytokines and metabolites, such as reactive oxygen intermediates, and the need to tailor the response depending on the pathogen (5). The inflammatory response is also influenced by previous physiological stimuli to the responding cells, which has lent credence to the concept of macrophage subsets. For example, LPS-stimulated synthesis of IL-12 by macrophages, which is required for the induction of interferon-␥ from NK cells (6), is inhibited by immune complex activation of Fc␥R. As a result, such type II macrophages (7) as antigen present...

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Enhanced inflammatory responses of chronic granulomatous disease leukocytes involve ROS‐independent activation of NF‐κB

et al. 2007

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Reactive oxygen species (ROS) generated by the cellular NADPH-oxidase are crucial for phagocytic killing of ingested microbes and have been implicated as signaling molecules in various processes. For example, ROS are thought to be involved in activation of the transcription factor NF-jB, central for mediating production of proinflammatory cytokines in response to inflammatory stimuli. Several studies have demonstrated that inhibitors of the NADPH-oxidase interfere with NF-jB activation and production of proinflammatory cytokines. Curiously, patients with chronic granulomatous disease (CGD), an immunodeficiency characterized by an inability to produce ROS, are not only predisposed to severe infections, but also frequently develop various inflammatory complications indicative of exaggerated inflammatory responses. Here, we show that human CGD leukocytes display a hyperinflammatory phenotype with increased production of proinflammatory cytokines in response to stimulation with Toll-like receptor agonists. The hyperinflammatory phenotype was also evident in mononuclear cells from CGD mice (gp91 phox-/-), but not in control cells in the presence of NADPHoxidase inhibitor diphenyleneiodonium, probably reflecting NADPH-oxidase-independent effects of the inhibitor. Furthermore, we show that the major steps involved in NFjB activation were intact in human CGD cells. These data indicate that ROS were nonessential for activation of NF-jB and their production may even attenuate inflammation.

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Identification of a p65 Peptide That Selectively Inhibits NF-κ B Activation Induced by Various Inflammatory Stimuli and Its Role in Down-regulation of NF-κB-mediated Gene Expression and Up-regulation of Apoptosis

Cited by 174 publications

References 61 publications

Suppression of NF-κB and NF-κB-regulated gene expression by sulforaphane and PEITC through IκBα, IKK pathway in human prostate cancer PC-3 cells

Suppression of NF-κB and NF-κB-regulated gene expression by sulforaphane and PEITC through IκBα, IKK pathway in human prostate cancer PC-3 cells

Interaction of TRAF6 with MAST205 Regulates NF-κB Activation and MAST205 Stability

Enhanced inflammatory responses of chronic granulomatous disease leukocytes involve ROS‐independent activation of NF‐κB

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