Transient and Selective NF-κB p65 Serine 536 Phosphorylation Induced by T Cell Costimulation Is Mediated by IκB Kinase β and Controls the Kinetics of p65 Nuclear Import

Mattioli, Ivan; Sebald, Andrea; Bucher, Cyril; Charles, Roch‐Philippe; Nakano, Hiroyasu; Doi, Takahiro; Kracht, Michael; Schmitz, M. Lienhard

doi:10.4049/jimmunol.172.10.6336

Cited by 214 publications

(190 citation statements)

References 66 publications

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“…Minocycline abrogates NF-kB p65 phosphorylation and nuclear translocation NF-kB transcriptional activity correlates with Ser 536 phosphorylation of the NF-kB subunit, p65, and its subsequent nuclear translocation (21). We therefore sought to investigate the effect of minocycline on these processes.…”

Section: Minocycline Suppresses Constitutive Nf-kb Activation In Ovarmentioning

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 Suppresses Constitutive Nf-kb Activation In Ovarmentioning

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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“…RelA/p65 by the IKK-related kinases IKK and TBK1 was previously demonstrated (8,14,(23)(24)(25)(26)47), although the physiological significance of these phosphorylation events remains to be previously determined. Recently, these two IKK-related kinases were shown to phosphorylate IRF-3 and IRF-7 transcription factors, thereby establishing their central role in the development of the innate antiviral response (17,18).…”

Section: Potential (Reviewed In Ref 21) Direct Phosphorylation Of Nf-bmentioning

confidence: 99%

“…In another study, IKK␤-mediated phosphorylation of RelA/p65 on Ser 536 in response to T cell costimulation resulted in the cytoplasmic retention of a RelA/p65 I B␣ complex. However, the role of IKK␤-mediated RelA/p65 phosphorylation on transcriptional activity was not established (23).…”

Section: Potential (Reviewed In Ref 21) Direct Phosphorylation Of Nf-bmentioning

confidence: 99%

“…21). Thus far, inducible phosphorylation of RelA/p65 at serine residues 276 or 311 in the Rel homology domain or serine residues 468, 529, and 536 in the TD have been observed following exposure of cells to various NF-B-inducing agents, culminating in the modulation of nuclear localization, DNA-binding affinity, coactivator/corepressor association, and transactivation capacity (14,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Inducible phosphorylation of cRel was also detected in response to PMA, CD28, or TNF-␣ treatment of T cells (34 -36); phosphorylation of Ser 471 in the TD has been reported to be involved in TNF-␣-induced activation of cRel (34,35), whereas Ser 451 in the TD of murine cRel serves as a phospho-acceptor site, although the physiological function of this event remains to be elucidated (37).…”

mentioning

confidence: 99%

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Nuclear Accumulation of cRel following C-Terminal phosphorylation by TBK1/IKKε

Harris

Oliere

Sharma

et al. 2006

The Journal of Immunology

102

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The NF-κB transcription factors are key regulators of immunomodulatory, cell cycle, and developmental gene regulation. NF-κB activity is mainly regulated through the phosphorylation of IκB by the IκB kinase (IKK) complex IKKαβγ, leading to proteasome-mediated degradation of IκB, nuclear translocation of NF-κB dimers, DNA binding, and gene induction. Additionally, direct posttranslational modifications of NF-κB p65 and cRel subunits involving C-terminal phosphorylation has been demonstrated. The noncanonical IKK-related homologs, TNFR-associated factor family member-associated NF-κB activator (TANK)-binding kinase (TBK)1 and IKKε, are also thought to play a role in NF-κB regulation, but their functions remain unclear. TBK1 and IKKε were recently described as essential regulators of IFN gene activation through direct phosphorylation of the IFN regulatory factor-3 and -7 transcription factors. In the present study, we sought to determine whether IKKε and TBK1 could modulate cRel activity via phosphorylation. TBK1 and IKKε directly phosphorylate the C-terminal domain of cRel in vitro and in vivo and regulate nuclear accumulation of cRel, independently of the classical IκB/IKK pathway. IκBα degradation is not affected, but rather IKKε-mediated phosphorylation of cRel leads to dissociation of the IκBα-cRel complex. These results illustrate a previously unrecognized aspect of cRel regulation, controlled by direct IKKε/TBK1 phosphorylation.

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“…44 Stimulation of this coreceptor alone is sufficient to induce weak IKK activation, which allows subsequent phosphorylation of IkB 45 and p65. 46 However, full NF-kB activation definitively requires input from CD28 as well as from the TCR. 45,47 Here, we will focus on the organization of the early signalling events, as the late steps of signal delivery into the IKK complex are already covered in this issue by the reviews of Israel and Tschopp.…”

Section: Coreceptor Signalling To Ikk/nf-jbmentioning

confidence: 99%

Controlling NF-κB activation in T cells by costimulatory receptors

Schmitz

Krappmann

2006

Cell Death Differ

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Full and productive activation of T lymphocytes relies on the simultaneous delivery of T cell receptor (TCR)-and coreceptor-derived signals. In naïve T cells engagement of the TCR alone causes anergy, while TCR triggering of preactivated T cells results in activation-induced cell death. Costimulatory signals are prominently mirrored by the activation of NF-kB, which needs input from the TCR as well as from coreceptors in order to be fully activated and to fulfil its crucial function in the immune response. Coreceptorgenerated signals tightly control the duration and amplitude of the NF-kB response. The activation of IkB kinase (IKK) complex at the contact zone between a T cell and an antigenpresenting cell offers the unique opportunity to study the spatial organization of IKK activation. Recent studies indicate that coreceptor pathways influence the threshold activities of many signalling mediators and thus act on multiple layers of the NF-kB pathway.

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Transient and Selective NF-κB p65 Serine 536 Phosphorylation Induced by T Cell Costimulation Is Mediated by IκB Kinase β and Controls the Kinetics of p65 Nuclear Import

Cited by 214 publications

References 66 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

Nuclear Accumulation of cRel following C-Terminal phosphorylation by TBK1/IKKε

Controlling NF-κB activation in T cells by costimulatory receptors

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