Signal-specific and phosphorylation-dependent RelB degradation: a potential mechanism of NF-κB control

Marienfeld, Ralf; Berberich‐Siebelt, Friederike; Berberich, Ingolf; Denk, Andrea; Serfling, Edgar; Neumann, Manfred

doi:10.1038/sj.onc.1204884

Cited by 69 publications

(73 citation statements)

References 22 publications

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“…The stimulus-induced RelB degradation is an alternative IkB-independent mechanism of NF-kB regulation known to occur not only in T cells but also in other lymphoid and non-lymphoid cells (Marienfeld et al, 2001(Marienfeld et al, , 2003. RelB is one of the five mammalian Rel proteins of which the NF-kB dimer is composed.…”

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confidence: 99%

“…Both processes differ in their kinetics with RelB degradation being delayed compared with IkB degradation. Further, RelB degradation is signal specific and cannot be induced by tumour necrosis factor-a, a potent activator of NF-kB (Marienfeld et al, 2001).…”

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confidence: 99%

“…Cells were either left unstimulated or were stimulated for 30 min with TPA (20ng/ml) and ionomycin (1 mM) (T þ I) (both from Sigma-Aldrich, St Louis MO, USA). Whole-cellular extracts (20 mg per lane) were immunoblotted as described earlier (Marienfeld et al, 2001) and analysed using a RelB-specific Ab (C19, sc-226; Santa Cruz Biotechnology). After stripping, the membranes were probed with a b-tubulin-specific Ab (#2128, Cell Signaling, Beverly, MA, USA) as a control for equal loading.…”

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confidence: 99%

“…After stripping, the membranes were probed with a b-tubulin-specific Ab (#2128, Cell Signaling, Beverly, MA, USA) as a control for equal loading. (e) Jurkat T cells pretreated with SB216763 (Sigma-Aldrich), a cell permeable GSK3-specific inhibitor (Forde and Dale, 2007) were subjected to subcellular fractionation as described earlier (Marienfeld et al, 2001). The protein extracts were analysed as described above.…”

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Glycogen synthase kinase-3β is a crucial mediator of signal-induced RelB degradation

et al. 2011

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The immediate early transcription factor nuclear factor (IjBs) kappa B (NF-jB) is crucially involved in the regulation of numerous physiological or pathophysiological processes such as inflammation and tumourigenesis. Therefore, the control of NF-jB activity, which is mainly regulated by signal-induced degradation of cytoplasmic inhibitors of NF-jB (IjBs), is of high relevance. One known alternative pathway of NF-jB regulation is the stimulus-induced proteasomal degradation of RelB, a component of the NF-jB dimer. Here, we identified the serine/threonine protein kinase glycogen synthase kinase-3b (GSK-3b) as a critical signalling component leading to RelB degradation. In Jurkat leukaemic T cells as well as in primary human T cells, tetradecanoylphorbolacetate/ionomycinand CD3/CD28-induced RelB degradation were impaired by a GSK-3b-specific pharmacological inhibitor, an ectopically expressed dominant-negative GSK-3b mutant and by small-interfering RNA-mediated silencing of GSK-3b expression. Furthermore, a physical interaction between RelB and GSK-3b was shown by co-immunoprecipitation, which was already notable in unstimulated cells. Most importantly, as demonstrated by in vitro kinase assays, human RelB is inducibly phosphorylated by GSK-3b, indicating a direct substrate-enzyme relationship. The serine residue 552 is a target of GSK-3b-mediated phosphorylation in vitro and in vivo. We conclude that GSK-3b is a crucial regulator of RelB degradation, stressing the relevant linkage between the NF-jB system and GSK-3b.

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Glycogen synthase kinase-3β is a crucial mediator of signal-induced RelB degradation

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“…Importantly, the physiological significance of RelB-phosphorylation has been elusive especially because a previous study based on analysis of T-cells reported that similar to the IkB molecules, the consequence of RelB-S573 phosphorylation is its degradation suggesting an inhibitory role for RelB 44,55 . On the contrary our results presented here indicate that phospho-RelB-S573 in MM In MM cells RelB and ERK1 constitutively interact with each other.…”

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Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth

et al. 2015

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Although transcriptional activation by NF-kB is well appreciated, physiological importance of transcriptional repression by NF-kB in cancer has remained elusive. Here we show that an HDAC4-RelB-p52 complex maintains repressive chromatin around proapoptotic genes Bim and BMF and regulates multiple myeloma (MM) survival and growth. Disruption of RelB-HDAC4 complex by a HDAC4-mimetic polypeptide blocks MM growth. RelB-p52 also represses BMF translation by regulating miR-221 expression. While the NIK-dependent activation of RelB-p52 in MM has been reported, we show that regardless of the activation status of NIK and the oncogenic events that cause plasma cell malignancy, several genetically diverse MM cells including Bortezomib-resistant MM cells are addicted to RelB-p52 for survival. Importantly, RelB is constitutively phosphorylated in MM and ERK1 is a RelB kinase. Phospho-RelB remains largely nuclear and is essential for Bim repression. Thus, ERK1-dependent regulation of nuclear RelB is critical for MM survival and explains the NIK-independent role of RelB in MM.

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RelB controls adaptive responses of astrocytes during sterile inflammation

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Waters

Biswas

et al. 2019

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In response to brain injury or infections, astrocytes become reactive, undergo striking morphological and functional changes, and secrete and respond to a spectrum of inflammatory mediators. We asked whether reactive astrocytes also display adaptive responses during sterile IL‐1β‐induced neuroinflammation, which may limit tissue injury associated with many disorders of the central nervous system. We found that astrocytes display days‐to‐weeks long specific tolerance of cytokine genes, which is coordinated by NF‐κB family member, RelB. However, in contrast to innate immune cells, astrocytic tolerance does not involve epigenetic silencing of the cytokine genes. Establishment of tolerance depends on persistent higher levels of RelB in tolerant astrocytes and its phosphorylation on serine 472. Mechanistically, this phosphorylation prevents efficient removal of RelB from cytokine promoters by IκBα and helps to establish tolerance. Importantly, ablation of RelB from astrocytes in mice abolishes tolerance during experimental neuroinflammation in vivo.

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Signal-specific and phosphorylation-dependent RelB degradation: a potential mechanism of NF-κB control

Cited by 69 publications

References 22 publications

Glycogen synthase kinase-3β is a crucial mediator of signal-induced RelB degradation

Glycogen synthase kinase-3β is a crucial mediator of signal-induced RelB degradation

Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth

RelB controls adaptive responses of astrocytes during sterile inflammation

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