Ubiquitination and Degradation of the Inhibitors of NF- B

Kanarek, Naama; London, Nir; Schueler‐Furman, Ora; Ben‐Neriah, Yinon

doi:10.1101/cshperspect.a000166

Cited by 116 publications

(102 citation statements)

References 119 publications

(139 reference statements)

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“…Knock-out approaches in mice have demonstrated that IκBα is essential, as its absence leads to death in the perinatal period [39], whereas knockout mice for the genes encoding IκBβ and IκBε are viable, suggesting they are dispensable for development [40, 41]. These observations are consistent with the higher level of expression (10 times as much mRNA as for IκBβ and IκBε, although all three genes are ubiquitously expressed) and the strong and rapid activation of IκBα (phosphorylation and degradation) [42, 43] (http://www.gtexportal.org). For a gain of function, the mutant NFKBIA allele must encode a mutant IκBα protein satisfying three conditions: the protein must be synthesized (although possibly at lower than normal levels), it must bind the Rel homology domain (RHD) of NF-κB heterodimers (p50, p65, c-REL) and it must not be degraded following the activation of cellular pathways that normally signal via NF-κB (Figure 2).…”

Section: Introductionmentioning

confidence: 79%

Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency

et al. 2017

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Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Fourteen unrelated patients have been reported since the identification of the first case in 2003. All mutations enhance the inhibitory activity of IκBα, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation. The mutations certainly or probably occurred de novo in 13 patients, whereas it was inherited from a parent with somatic mosaicism in one patient. Eleven mutations, belonging to two groups, have been identified: (i) missense mutations affecting S32, S36, or neighboring residues (8 mutations, 11 patients) and (ii) nonsense mutations upstream from S32 associated with the reinitiation of translation downstream from S36 (3 mutations, 3 patients). Thirteen patients had developmental features of EDA, the severity and nature of which differed between cases. All patient cells tested displayed impaired NF-κB-mediated responses to the stimulation of various surface receptors involved in cell-intrinsic (fibroblasts), innate (monocytes), and adaptive (B and T cells) immunity, including TLRs, IL-1Rs, TNFRs, TCR, and BCR. All patients have profound B-cell deficiency. Specific immunological features, found in some, but not all patients, include a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells. The patients had various pyogenic, mycobacterial, fungal, and viral severe infections. Patients with a missense mutation tend to display more severe phenotypes, probably due to higher levels of GOF proteins. In the absence of hematopoietic stem cell transplantation (HSCT), this condition can cause death before the age of 1 year (one child). Two survivors are on prophylaxis (at 9 and 22 years). Six children died after HSCT. Five survived, four of whom are on prophylaxis (3 to 21 years post HSCT), whereas one is well with no prophylaxis. Heterozygous GOF mutations in IκBα underlie a severe and syndromic immunodeficiency, the inter-individual variability of which might partly be ascribed to the dichotomy of missense and nonsense mutations, and the hematopoietic component of which can be rescued by HSCT.

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Section: Introductionmentioning

confidence: 79%

Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency

et al. 2017

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“…IKKb substrates include p105, the precursor of the p50 NF-kB1 transcription factor, as well as the IkB proteins that sequester NF-kB transcription factors in the cytosol. Phosphorylation by IKKb targets these substrates for K48-linked polyubiquitylation by the E3 ubiquitin ligase SCF b-TrCP and subsequent proteasomal degradation (Kanarek et al 2010). Degradation of p105, which exists in a complex with the kinase Tpl2, activates a Tpl2-MEK1-ERK kinase cascade that leads to the induction of genes such as Ptgs2 by the CREB/ATF family of transcription factors (Banerjee and Gerondakis 2007).…”

Section: Genesmentioning

confidence: 99%

Signaling in Innate Immunity and Inflammation

Newton¹,

Dixit²

2012

Cold Spring Harbor Perspectives in Biology

1,278

1,017

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“…The detailed mechanisms of IKK-mediated NF-κB activation are discussed in several reviews. 123–125 Indeed, EGFR TKI resistance via NF-κB signaling was identified through a non-biased RNA interference screen in lung cancer cells with mutated EGFR . 126 Interestingly, STAT3, which can be activated by EGFR, also promotes nuclear localization and activation of NF-κB via p300-mediated acetylation.…”

Section: Possible Contribution Of Other Signaling Pathways In Tki Resmentioning

confidence: 99%

Signaling cross-talk in the resistance to HER family receptor targeted therapy

et al. 2013

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Epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) have an important role in the initiation and progression of various types of cancer. Inhibitors targeting these receptor tyrosine kinases are some of the most successful targeted anticancer drugs widely used for cancer treatment; however, cancer cells have mechanisms of intrinsic and acquired drug resistance that pose as major obstacles in drug efficacy. Extensive studies from both clinical and laboratory research have identified several molecular mechanisms underlying resistance. Among them is the role of signaling cross-talk between the EGFR/HER2 and other signaling pathways. In this review, we focus particularly on this signaling cross-talk at the receptor, mediator and effector levels, and further discuss alternative approaches to overcome resistance. In addition to well-recognized signaling cross-talk involved in the resistance, we also introduce the cross-talk between EGFR/HER2-mediated pathways and pathways triggered by other types of receptors, including those of the Notch, Wnt and TNFR/IKK/NF-κB pathways, and discuss the potential role of targeting this cross-talk to sensitize cells to EGFR/HER2 inhibitors.

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Ubiquitination and Degradation of the Inhibitors of NF- B

Cited by 116 publications

References 119 publications

Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency

Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency

Signaling in Innate Immunity and Inflammation

Signaling cross-talk in the resistance to HER family receptor targeted therapy

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