Noncanonical NF-κB Signaling in Health and Disease

Cildir, Gökhan; Low, Kee Chung; Tergaonkar, Vinay

doi:10.1016/j.molmed.2016.03.002

Cited by 243 publications

(242 citation statements)

References 134 publications

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“…47,48,49 In addition, non-canonical NF-kB pathway is also found to be instrumental in the pathogenesis of various cancers as well as immune disorders. 50 The current investigation suggests that GNL3L, putative nucleolar GTPase upregulates the expression of p50 which is a key mediator of the non-canonical NF-kB pathway. Furthermore, accumulating evidences suggest the cross-talk of Akt and ERK/MAPK signaling on NF-kB pathway 51 but the role of GNL3L and LDOC1 on Akt/ERK/MAPK signaling pathway remains an open question.…”

Section: Discussionmentioning

confidence: 77%

Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-κB) signaling during cell proliferation

et al. 2016

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Guanine nucleotide binding protein-like 3-like (GNL3L) is an evolutionarily conserved putative nucleolar GTPase belonging to the HSR1-MMR1 family. In the present study, using protein-protein interaction assays, we show that Leucine Zipper Down-regulated in Cancer-1 (LDOC1) is a novel interacting partner of GNL3L. Furthermore, our results reveal that ectopic expression of LDOC1 destabilizes endogenous GNL3L levels and down modulates GNL3L-induced cell proliferation, in contrast, the knockdown of LDOC1 potentiates cell proliferation upon GNL3L expression. Interestingly, GNL3L upregulates NF-kB dependent transcriptional activity by modulating the expression of NF-kB subunit p65, which is reversed upon coexpression of LDOC1 with GNL3L. GNL3L also potentiates TNF-a mediated NF-kB activity. In addition, antiapoptotic function of GNL3L is impaired upon p65 knockdown, suggesting its critical role in GNL3L mediated cell proliferation/survival. An inverse correlation of GNL3L and LDOC1 expression profiles in various tumor tissues from BioXpress database indicate their critical role in cancer. Collectively, our data provides evidence that GNL3L-LDOC1 interplay regulates cell proliferation through the modulation of NFkB pathway during tumorigenesis.

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Section: Discussionmentioning

confidence: 77%

Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-κB) signaling during cell proliferation

et al. 2016

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“…[345] Activated IκB kinase β (IKKβ) phosphorylates the inhibitor of NF-κB (IκB), which binds NF-κB to inhibit its function, leading to the degradation of IκB and free of NF-κB entering into the nucleus where it activates various target genes. [678] IKKβ can also phosphorylate p53, which is a critical tumor suppressor that activates lots of genes including p21, Bax, and Puma at the transcriptional level, promoting its degradation by β-TrCP. [9] Loss of IKKβ activity increases the stability of p53 and expression of p21 resulting in cell cycle arrest and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

IκB kinase β Mediating the Downregulation of p53 and p21 by Lipopolysaccharide in Human Papillomavirus 16+ Cervical Cancer Cells

Zhang

Tian

Tan

et al. 2016

Chinese Medical Journal

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Background:Cervical cancer is the second most common cancer of woman in the world, and human papillomavirus (HPV) infection plays an important role in the development of most of the cases. IκB kinase β (IKKβ) is a kinase-mediating nuclear factor kappa B (NF-κB) activation by phosphorylating the inhibitor of NF-κB (IκB) and is related by some diseases caused by virus infection. However, there is little known about the correlation between IKKβ and HPV infection in cervical cancer. This study aimed to investigate the expression of IKKβ protein in cervical cancer tissues and effects of inflammation on HPV positive or negative cervical cancer cells through detecting the expression of IKKβ, IκBα, p53, and p21 proteins after treated with lipopolysaccharide (LPS) to mimic bacterial infection. We also examined the effects of LPS on cervical cancer cells after blocking IKKβ with pharmacological inhibitor.Methods:Thirty-six matched specimens of cervical cancer and adjacent normal tissues were collected and analyzed in the study. The expression of IKKβ in the tissue specimens was determined by immunohistochemical staining. In addition, Western blot was used to detect the expression level changes of IKKβ, IκBα, p53, and p21 after LPS stimulated in the HPV16+ (SiHa) and HPV16− (C33A) cervical cancer cell lines. Furthermore, the effects of IKKβ inhibitor SC-514 on LPS-induced expression change of these proteins were investigated.Results:The expression of IKKβ was higher in cervical cancer than adjacent normal tissues, and there was no significant difference between tumor differentiation, size, and invasive depth with IKKβ expression. The LPS, which increased the expression level of IKKβ protein but decreased in the IκBα, p53 and p21 proteins, was illustrated in HPV16+ (SiHa) but not in HPV16− (C33A) cells. Moreover, IKKβ inhibitor SC-514 totally reversed the upregulation of IKKβ and downregulation of p53 and p21 by LPS in SiHa cells.Conclusions:IKKβ may mediate the downregulation of p53 and p21 by LPS in HPV16+ cervical cancer cells.

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“…Upon IKK activation, IκB is phosphorylated and, subsequently, targeted for rapid proteasomal degradation, thus liberating NF-κB for nuclear translocation, enhanced DNA binding and transcriptional regulation3. NEMO is an adaptor protein involved in activation of the IKK kinases and has been shown to be critically important for the canonical4 and stress-induced NF-κB pathway5. Ablation of NEMO in mice resulted in a lack of detectable NF-κB DNA-binding activity and a lethal embryonic phenotype because of severe liver damage due to massive apoptosis6.…”

mentioning

confidence: 99%

GSK-3β controls NF-kappaB activity via IKKγ/NEMO

Medunjanin

Schleithoff

Fiegehenn

et al. 2016

Sci Rep

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The NF-κB signaling pathway is central for the innate immune response and its deregulation is found in multiple disorders such as autoimmune, chronic inflammatory and metabolic diseases. IKKγ/NEMO is essential for NF-κB activation and NEMO dysfunction in humans has been linked to so-called progeria syndromes, which are characterized by advanced ageing due to age-dependent inflammatory diseases. It has been suggested that glycogen synthase kinase-3β (GSK-3β) participates in NF-κB regulation but the exact mechanism remained incompletely understood. In this study, we identified NEMO as a GSK-3β substrate that is phosphorylated at serine 8, 17, 31 and 43 located within its N-terminal domain. The kinase forms a complex with wild-type NEMO while point mutations of NEMO at the specific serines abrogated GSK-3β binding and subsequent phosphorylation of NEMO resulting in its destabilization. However, K63-linked polyubiquitination was augmented in mutated NEMO explaining an increased binding to IKKα and IKKβ. Even IκBα was found degraded. Still, TNFα-stimulated NF-κB activation was impaired pointing towards an un-controlled signalling process. Our data suggest that GSK-3β is critically important for ordered NF-κB signalling through modulation of NEMO phosphorylation.

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Noncanonical NF-κB Signaling in Health and Disease

Cited by 243 publications

References 134 publications

Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-κB) signaling during cell proliferation

Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-κB) signaling during cell proliferation

IκB kinase β Mediating the Downregulation of p53 and p21 by Lipopolysaccharide in Human Papillomavirus 16+ Cervical Cancer Cells

GSK-3β controls NF-kappaB activity via IKKγ/NEMO

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