Crosstalk via the NF-κB signaling system

Basak, Soumen; Hoffmann, Alexander

doi:10.1016/j.cytogfr.2008.04.005

Cited by 154 publications

(122 citation statements)

References 63 publications

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“…Translocation of NF-kB to the nucleus succeeds the proteolytic degradation of the NF-kB-associated inhibitory protein; IkBa (22). Therefore, we next examined whether minocycline-induced NF-kB inhibition is associated with inhibition of IkBa degradation.…”

Section: Minocycline Inhibits Ikba Degradation and Phosphorylationmentioning

confidence: 99%

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

Ataie-Kachoie

Badar

Morris

et al. 2013

Molecular Cancer Research

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Substantial evidence supports the critical role of NF-kB in ovarian cancer. Minocycline, a tetracycline, has been shown to exhibit beneficial effects in this malignancy through regulation of a cohort of genes that overlap significantly with the NF-kB transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-kB signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-kB activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of IkBa kinase (IKK) activation, IkBa phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-b-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-b and TAK1. Further studies demonstrated that minocycline downregulated TGF-b1 expression. Enforced TGF-b1 expression induced NF-kB activity, and minocycline rescued this effect. Consistent with this finding, TGF-b1 knockdown suppressed NF-kB activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-kB activity is mediated, in part, through inhibition of TGF-b1. Furthermore, the influence of minocycline on NF-kB pathway activation was examined in female nude mice harboring intraperitoneal OVCAR-3 tumors. Both acute and chronic administration of minocycline led to suppression of p65 phosphorylation and nuclear translocation accompanied by downregulation of NF-kB activity and endogenous protein levels of its target gene products. These data reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-b-NF-kB axis in ovarian cancer.

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Section: Minocycline Inhibits Ikba Degradation and Phosphorylationmentioning

confidence: 99%

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

Ataie-Kachoie

Badar

Morris

et al. 2013

Molecular Cancer Research

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“…As a mediator of inflammatory tolerance, it may regulate RelA activities during T cell activation (19,20), osteoclastogenesis (21) and lymph node formation (22). Similarly, I B␦ is likely to play a role in providing a brake for cancer-associated chronically-elevated IKK2 signaling (23). Indeed, mutations that cause C-terminal truncations of p100 are found in some B and T cell malignancies (24), and signals impinging on IKK1 that are able to relieve such attenuation of RelA:p50 play a role in some Hodgkin lymphoma cells (25) and are found to be elevated via mutations found in multiple myeloma (26,27).…”

Section: Discussionmentioning

confidence: 99%

Kinetic control of negative feedback regulators of NF-κB/RelA determines their pathogen- and cytokine-receptor signaling specificity

Shih

Kearns

Basak

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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119

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Mammalian signaling networks contain an abundance of negative feedback regulators that may have overlapping (''fail-safe'') or specific functions. Within the NF-B signaling module, I B␣ is known as a negative feedback regulator, but the newly characterized inhibitor I B␦ is also inducibly expressed in response to inflammatory stimuli. To examine I B␦'s roles in inflammatory signaling, we mathematically modeled the 4-I B-containing NF-B signaling module and developed a computational phenotyping methodology of general applicability. We found that I B␦, like I B␣, can provide negative feedback, but each functions stimulusspecifically. Whereas I B␦ attenuates persistent, pathogen-triggered signals mediated by TLRs, the more prominent I B␣ does not. Instead, I B␣, which functions more rapidly, is primarily involved in determining the temporal profile of NF-B signaling in response to cytokines that serve intercellular communication. Indeed, when removing the inducing cytokine stimulus by compound deficiency of the tnf gene, we found that the lethality of i b␣ ؊/؊ mouse was rescued. Finally, we found that I B␦ provides signaling memory owing to its long half-life; it integrates the inflammatory history of the cell to dampen NF-B responsiveness during sequential stimulation events.inflammation ͉ mathematical modeling ͉ NF-kappaB ͉ pathogen

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“…Maturation of p50 from p105 is co-translationally regulated [22], while that of p52 is signal inducible [23,24]. These five members can form various homo-and heterodimers with one another to control tissue-and signal-specific gene expression programs (reviewed in [25]). Dimers containing RelA are kept inactive in the cytoplasm by association with a member of the IκB family of inhibitors, such as IκBα.…”

Section: The Ikk-nf-κb Signaling Systemmentioning

confidence: 99%

Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

2010

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A large body of literature describes elaborate NF-κB signaling networks induced by inflammatory and immune signals. Decades of research has revealed that transcriptionally functional NF-κB dimers are activated by two major pathways, canonical and non-canonical. Both pathways involve the release of NF-κB dimers from inactive cytoplasmic complexes to cause their nuclear translocation to modulate gene expression programs and biological responses. NF-κB is also responsive to genotoxic agents; however, signal communication networks that are initiated in the nucleus following DNA damage induction are less defined. Evidence in the literature supports the presence of such signaling pathways induced by multiple distinct genotoxic agents, resulting in the activation of cytoplasmic IKK complex. An example is a pathway that involves the DNA damage-responsive kinase ataxia telangiectasia mutated (ATM) and a series of post-translational modifications of NF-κB essential modulator (NEMO) in the nucleus of a genotoxinexposed cell. Recent evidence also suggests that this nuclear-initiated NF-κB signaling pathway plays significant physiological and pathological roles, particularly in lymphocyte development and human cancer progression. This review will summarize these new developments, while identifying significant unanswered questions and providing new hypotheses that may be addressed in future studies.

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Crosstalk via the NF-κB signaling system

Cited by 154 publications

References 63 publications

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

Kinetic control of negative feedback regulators of NF-κB/RelA determines their pathogen- and cytokine-receptor signaling specificity

Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

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