IκB-independent control of NF-κB activity by modulatory phosphorylations

Schmitz, M. Lienhard; Bacher, Susanne; Kracht, Michael

doi:10.1016/s0968-0004(00)01753-9

Cited by 220 publications

(172 citation statements)

References 35 publications

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“…This is similar to what we have previously observed for Bcr [22]. However, an alternate mechanism for activating NF-κB involves phosphorylation of the transactivation domain [37][38][39]. Several studies have shown that the transcriptional activity of NF-κB is increased by phosphorylation at ser276, ser311, ser529 or ser536 [40][41][42][43].…”

Section: Discussionsupporting

confidence: 89%

ROCK I-mediated activation of NF-κB by RhoB

Rodrı́guez

Sahay

Olabisi

et al. 2007

Cellular Signalling

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RhoB is a short-lived protein whose expression is increased by a variety of extra-cellular stimuli including UV irradiation, epidermal growth factor (EGF) and transforming growth factor β (TGF-β). Whereas most Rho proteins are modified by the covalent attachment of a geranylgeranyl group, RhoB is unique in that it can exist in either a geranylgeranylated (RhoB-GG) or a farnesylated (RhoB-F) form. Although each form is proposed to have different cellular functions, the signaling events that underlie these differences are poorly understood. Here we show that RhoB can activate NF-κB signaling in multiple cell types. Whereas RhoB-F is a potent activator of NF-κB, much weaker activation is observed for RhoB-GG, RhoA, and RhoC. NF-κB activation by RhoB is not associated with increased nuclear translocation of RelA/p65, but rather, by modification of the RelA/p65 transactivation domain. Activation of NF-κB by RhoB is dependent upon ROCK I but not PRK I. Thus, ROCK I cooperates with RhoB to activate NF-κB, and suppression of ROCK I activity by genetic or pharmacological inhibitors blocks NF-κB activation. Suppression of RhoB activity by dominant-inhibitory mutants, or siRNA, blocks NF-κB activation by Bcr, and TSG101, but not by TNFα or oncogenic Ras. Collectively, these observations suggest the existence of an endosomeassociated pathway for NF-κB activation that is preferentially regulated by the farnesylated form of RhoB.

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Section: Discussionsupporting

confidence: 89%

ROCK I-mediated activation of NF-κB by RhoB

Rodrı́guez

Sahay

Olabisi

et al. 2007

Cellular Signalling

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“…Furthermore, p38 may modulate gene expression at the level of transactivation by interacting with components of the enhanceosome, such as the transcriptional coactivator CBP/p300 (21). Highlighting the regulatory complexity, mitogen-and stress-activated protein kinase-1 (MSK1), which acts downstream of p38, has been identified to phosphorylate the NF-B/Rel family member p65 as well as components of the chromatin environment, thereby interfering with NF-B-dependent gene transcription (41,42). Our data demonstrate that p38, like NF-B, is activated in a delayed kinetic upon exposure to C. albicans.…”

Section: Discussionmentioning

confidence: 99%

Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells

Müller

Viemann²,

Schmidt

et al. 2007

The Journal of Immunology

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Endothelial cells (EC) actively participate in the innate defense against microbial pathogens. Under unfavorable conditions, defense reactions can turn life threatening resulting in sepsis. We therefore studied the so far largely unknown EC reaction patterns to the fungal pathogen Candida albicans, which is a major cause of lethality in septic patients. Using oligonucleotide microarray analysis, we identified 56 genes that were transcriptionally up-regulated and 69 genes that were suppressed upon exposure of ECs to C. albicans. The most significantly up-regulated transcripts were found in gene ontology groups comprising the following categories: chemotaxis/migration; cell death and proliferation; signaling; transcriptional regulation; and cell-cell contacts/intercellular signaling. Further examination of candidate signaling cascades established a central role of the proinflammatory NF-κB pathway in the regulation of the Candida-modulated transcriptome of ECs. As a second major regulatory pathway we identified the stress-activated p38 MAPK pathway, which critically contributes to the regulation of selected Candida target genes such as CXCL8/IL-8. Depletion of MyD88 and IL-1R-associated kinase-1 by RNA interference demonstrates that Candida-induced NF-κB activation is mediated by pattern recognition receptor signaling. Additional experiments suggest that C. albicans-induced CXCL8/IL-8 expression is mediated by TLR3 rather than TLR2 and TLR4, which previously have been implicated with MyD88/IκB kinase-2/NF-κB activation by this fungus in other systems. Our study provides the first comprehensive analysis of endothelial gene responses to C. albicans and presents novel insights into the complex signaling patterns triggered by this important pathogen.

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“…We did not observe, in the DaPKC-depleted cells, a strong inhibition of Dorsal or Dif nuclear translocation, which suggests that the role of DaPKC is independent of the previously characterized role for Dorsal phosphorylation in regulating nuclear translocation. Based on experiments in mammalian systems, which demonstrate that p65 transcriptional activity must be stimulated by phosphorylation (31), it is possible that the residues that control the transcriptional activities of both Dorsal and Dif are different from those controlling the nuclear import of the protein. It is also possible that DaPKC-mediated phosphorylation has a subtle, yet important, role in the nuclear translocation of Dif and/or Dorsal.…”

Section: Discussionmentioning

confidence: 99%