Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

TNFSF14/LIGHT, a Non-Canonical NF-?B Stimulus, Induces the HIF Pathway.

ABSTRACT: Non-canonical NF-?B signalling plays important roles in the development and function of the immune system but it also is deregulated in a number of inflammatory diseases. Although, NF-?B and HIF crosstalk has been documented, this has only been described following canonical NF-?B stimulation, involving RelA/p50 and the HIF-1 dimer. Here, we report that the non-canonical inducer TNFSF14/LIGHT leads to HIF induction and activation in cancer cells. We demonstrate that only HIF-2? is induced at the transcriptional level following non-canonical NF-?B activation, via a mechanism that is dependent on the p52 subunit. Furthermore, we demonstrate that p52 can bind to the HIF-2? promoter in cells. These results indicate that non-canonical NF-?B can lead to HIF signalling implicating HIF-2? as one of the downstream effectors of this pathway in cells.

SUBMITTER: D'Ignazio L

PROVIDER: S-EPMC6116154 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

TNFSF14/LIGHT, a Non-Canonical NF-κB Stimulus, Induces the HIF Pathway.

D'Ignazio Laura L Batie Michael M Rocha Sonia S

Cells 20180808 8

Non-canonical NF-κB signalling plays important roles in the development and function of the immune system but it also is deregulated in a number of inflammatory diseases. Although, NF-κB and HIF crosstalk has been documented, this has only been described following canonical NF-κB stimulation, involving RelA/p50 and the HIF-1 dimer. Here, we report that the non-canonical inducer TNFSF14/LIGHT leads to HIF induction and activation in cancer cells. We demonstrate that only HIF-2α is induced at the ...[more]

PMID: 30096845

Similar Datasets

Non-canonical NF-κB signaling pathway.

Project description:The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex. This pathway depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor. A central signaling component of the non-canonical pathway is NF-κB-inducing kinase (NIK), which integrates signals from a subset of TNF receptor family members and activates a downstream kinase, IκB kinase-α (IKKα), for triggering p100 phosphorylation and processing. A unique mechanism of NIK regulation is through its fate control: the basal level of NIK is kept low by a TRAF-cIAP destruction complex and signal-induced non-canonical NF-κB signaling involves NIK stabilization. Tight control of the fate of NIK is important, since deregulated NIK accumulation is associated with lymphoid malignancies.

| S-EPMC3193406 | biostudies-other

Her2 activates NF-kappaB and induces invasion through the canonical pathway involving IKKalpha.

Project description:The membrane bound receptor tyrosine kinase Her2 is overexpressed in approximately 30% of human breast cancers, which correlates with poor prognosis. Her2-induced signaling pathways include MAPK and PI3K/Akt, of which the latter has been shown to be critical for Her2(+) breast cancer cell growth and survival. In addition, the NF-kappaB pathway has been shown to be activated downstream of Her2 overexpression; however, the mechanisms leading to this activation are not currently clear. Using Her2(+)/ER(-) breast cancer cells, we show that Her2 activates NF-kappaB through the canonical pathway which, surprisingly, involves IKKalpha. Knockdown of IKKalpha led to a significant decrease in transcription levels of multiple NF-kappaB-regulated cytokine and chemokine genes. siRNA-mediated knockdown of IKKalpha resulted in a decrease in cancer cell invasion, but had no effect on cell proliferation. Inhibition of the PI3K/Akt pathway had no effect on NF-kappaB activation, but significantly inhibited cell proliferation. Our study suggests different roles for the NF-kappaB and PI3K pathways downstream of Her2, leading to changes in invasion and proliferation of breast cancer cells. In addition this work indicates the importance of IKKalpha as a mediator of Her2-induced tumor progression.

| S-EPMC2829103 | biostudies-literature

Tissue transglutaminase constitutively activates HIF-1? promoter and nuclear factor-?B via a non-canonical pathway.

Project description:Constitutive activation of nuclear factor kappa B (NF-?B) has been linked with carcinogenesis and cancer progression, including metastasis, chemoresistance, and radiation resistance. However, the molecular mechanisms that result in constitutive activation of NF-?B are poorly understood. Here we show that chronic expression of the pro-inflammatory protein tissue transglutaminase (TG2) reprograms the transcription regulatory network in epithelial cells via constitutive activation of NF-?B. TG2-induced NF-?B binds the functional NF-?B binding site in hypoxia-inducible factor-1 (HIF-1?) promoter and results in its increased expression at transcription and protein levels even under normoxic conditions. TG2/NF-?B-induced HIF-1 was deemed essential for increased expression of some transcription repressors, like Zeb1, Zeb2, Snail, and Twist. Unlike tumor necrosis factor-alpha (TNF?), TG2 did not require I?B kinase (IKK) for NF-?B activation. Our data suggest that TG2 binds with I?B? and results in its rapid degradation via a non-proteasomal pathway. Importantly, the catalytically inactive (C277S) mutant form of TG2 was as effective as was wild-type TG2 in activating NF-?B and inducing HIF-1 expression. We also found that TG2 interacted with p65/RelA protein, both in the cytosolic and the nuclear compartment. The TG2/p65(NF-?B) complex binds to the HIF-1 promoter and induced its transcriptional regulation. Inhibition of TG2 or p65/RelA also inhibited the HIF-1? expression and attenuated Zeb1, Zeb2, and Twist expression. To our knowledge, these findings show for the first time a direct link between TG2, NF-?B, and HIF-1?, demonstrating TG2's important role in cancer progression.

| S-EPMC3501523 | biostudies-literature

Targeting the Non-Canonical NF-κB Pathway in Chronic Lymphocytic Leukemia and Multiple Myeloma.

Project description:In this study, we evaluated an NF-κB inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B- and T-lymphocytes. Basal NF-κB subunit activity was characterized using an enzyme linked immunosorbent assay (ELISA), and the effects of NIK inhibition were then assessed in terms of cytotoxicity and the expression of nuclear NF-κB subunits following monoculture and co-culture with CD40L-expressing fibroblasts, as a model of the lymphoid niche. CW15337 induced a dose-dependent increase in apoptosis, and nuclear expression of the non-canonical NF-κB subunit, p52, was correlated with sensitivity to CW15337 (p = 0.01; r2 = 0.39). Co-culture on CD40L-expressing cells induced both canonical and non-canonical subunit expression in nuclear extracts, which promoted in vitro resistance against fludarabine and ABT-199 (venetoclax) but not CW15337. Furthermore, the combination of CW15337 with fludarabine or ABT-199 showed cytotoxic synergy. Mechanistically, CW15337 caused the selective inhibition of non-canonical NF-κB subunits and the transcriptional repression of BCL2L1, BCL2A1 and MCL1 gene transcription. Taken together, these data suggest that the NIK inhibitor, CW15337, exerts its effects via suppression of the non-canonical NF-κB signaling pathway, which reverses BCL2 family-mediated resistance in the context of CD40L stimulation.

| S-EPMC8946537 | biostudies-literature

Reelin induces Erk1/2 signaling in cortical neurons through a non-canonical pathway.

Project description:Reelin is an extracellular protein that controls many aspects of pre- and postnatal brain development and function. The molecular mechanisms that mediate postnatal activities of Reelin are not well understood. Here, we first set out to express and purify the full length Reelin protein and a biologically active central fragment. Second, we investigated in detail the signal transduction mechanisms elicited by these purified Reelin proteins in cortical neurons. Unexpectedly, we discovered that the full-length Reelin moiety, but not the central fragment, is capable of activating Erk1/2 signaling, leading to increased p90RSK phosphorylation and the induction of immediate-early gene expression. Remarkably, Erk1/2 activation is not mediated by the canonical signal transduction pathway, involving ApoER2/VLDLR and Dab1, that mediates other functions of Reelin in early brain development. The activation of Erk1/2 signaling likely contributes to the modulation of neuronal maturation and synaptic plasticity by Reelin in the postnatal and adult brain.

| S-EPMC4106344 | biostudies-literature

Involvement of A20 in the molecular switch that activates the non-canonical NF-?B pathway.

Project description:The non-canonical NF-?B pathway is crucial for the immune system. A critical event in activation of the non-canonical pathway is the attenuation of NF-?B-inducing kinase (NIK) degradation, which is promoted by continuous polyubiquitination of NIK catalyzed by the NIK ubiquitin-ligase complex composed of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2), TNF receptor-associated factor 2 (TRAF2), and TRAF3. However, the molecular mechanism of stimulation-dependent NIK stabilization remains poorly understood. Here, we show that A20, a ubiquitin-editing enzyme, promotes efficient activation of the non-canonical pathway independent of its catalytic activity. A20 directly binds to cIAP1 through the seventh zinc finger of A20, resulting in dissociation of the TRAF2/TRAF3 interaction, thereby inactivating the ligase complex to stabilize NIK. Given that A20 negatively regulates the canonical pathway, A20 is likely involved in the molecular switch that promotes the transition from canonical to non-canonical activation for proper control of the immune system.

| S-EPMC3764444 | biostudies-literature

HIF-2α regulates non-canonical glutamine metabolism via activation of PI3K/mTORC2 pathway in human pancreatic ductal adenocarcinoma.

Project description:Hypoxia-inducible factor-2α (HIF-2α) plays an important role in increasing cancer progression and distant metastasis in a variety of tumour types. We aimed to investigate its biological function and clinical significance in human pancreatic ductal adenocarcinoma (PDAC). A total of 283 paired PDAC tissues and adjacent normal tissues were collected from patients who underwent surgery or biopsy at Sun Yat-sen Memorial Hospital between February 2004 and October 2016. In this study, we noted that HIF-2α expression was significantly up-regulated in PDAC, positively associated with disease stage, lymph-node metastasis and patient survival, and identified as an independent prognostic factor of PDAC patients. We demonstrated that HIF-2α silencing could reduce proliferation, migration and invasion of PDAC cells in vitro. The similar effect on growth was demonstrated in vivo. Furthermore, we noted that knock-down of HIF-2α significantly decreased the expression of glutamate oxaloacetate transaminase 1 (GOT1). Importantly, we confirmed that the PI3K/mTORC2 pathway promoted GOT1 expression by targeting HIF-2α. Our study validated HIF-2α was an important factor in PDAC progression and poor prognosis and may promote non-canonical glutamine metabolism via activation of PI3K/mTORC2 pathway. Targeting HIF-2α represents a novel prognostic biomarker and therapeutic target for patients with PDAC.

| S-EPMC5661146 | biostudies-literature

NF-κB inducing kinase, a central signaling component of the non-canonical pathway of NF-κB, contributes to ovarian cancer progression.

Project description:Ovarian cancer is one of the leading causes of female death and the development of novel therapeutic approaches is urgently required. Nuclear factor-κB (NF-κB) is constitutively activated in several types of cancer including ovarian cancer and is known to support the survival of cancer cells. However, molecular mechanisms of persistent activation of NF-κB in ovarian cancer remain largely unknown. We report here that, in addition to the previously reported canonical activation, NF-κB is activated through the noncanonical pathway in ovarian cancer cells. RNA interference-mediated silencing of NF-κB inducing kinase (NIK), a central regulator of the noncanonical pathway, reduced the NF-κB2/p52 DNA binding activity and NF-κB-dependent reporter gene expression as well as NF-κB target gene expression. Notably, anchorage-dependent and -independent cell growth was impaired in NIK-depleted cells. Depletion of NIK also suppressed tumor formation in the nude mouse xenograft assay. These results indicate that NIK plays a key role in constitutive NF-κB activation and the progression of ovarian cancer cells and suggest that NIK represents an attractive therapeutic target for ovarian cancer.

| S-EPMC3922808 | biostudies-literature

Canonical and non-canonical NF-?B signaling promotes breast cancer tumor-initiating cells.

Project description:Tumor-initiating cells (TICs) are a sub-population of cells that exhibit a robust ability to self-renew and contribute to the formation of primary tumors, the relapse of previously treated tumors and the development of metastases. TICs have been identified in various tumors including those of the breast, and are particularly enriched in the basal-like and claudin-low subtypes of breast cancer. The signaling pathways that contribute to the function and maintenance of TICs are under intense study. We explored the potential involvement of the nuclear factor-?B (NF-?B) family of transcription factors in TICs in cell lines that are representative of basal-like and claudin-low breast cancer. NF-?B was found to be activated in breast cancer cells that form tumorspheres efficiently. Moreover, both canonical and non-canonical NF-?B signaling is required for these cells to self-renew in vitro and to form xenograft tumors efficiently in vivo using limiting dilutions of cells. Consistent with this fact, canonical and non-canonical NF-?B signaling is activated in TICs isolated from breast cancer cell lines. Experimental results indicate that NF-?B promotes the function of TICs by stimulating epithelial-to-mesenchymal transition and by upregulating the expression of the inflammatory cytokines interleukin-1? and interleukin-6. The results suggest the use of NF-?B inhibitors for clinical therapy of certain breast cancers.

| S-EPMC4425414 | biostudies-literature

Excessive Activation of TLR4/NF-?B Interactively Suppresses the Canonical Wnt/?-catenin Pathway and Induces SANFH in SD Rats.

Project description:Nuclear factor-kappa B (NF-?B) interactively affects the Wnt/?-catenin pathway and is closely related to different diseases. However, such crosstalk effect in steroid-associated necrosis of femoral head (SANFH) has not been fully explored and evaluated. In this study, early-stage SANFH was induced by two doses of lipopolysaccharide (LPS, 2?mg/kg/day) and three doses of methylprednisolone (MPS, 40?mg/kg/day). LPS and pyrrolidine dithiocarbamate (PDTC) were administered to activate the TLR4/NF-?B pathway and selectively block the activation of NF-?B, respectively. Results showed that PDTC treatment significantly reduced NF-?B expression, diminished inflammation, and effectively decreased bone resorption processes (osteoclastogenesis, adipogenesis, and apoptosis), which were evidently reinforced after osteonecrosis induction. Moreover, PDTC remarkably increased the interfered Wnt/?-catenin pathway and elevated bone formation processes (osteogenesis and angiogenesis). Ultimately, PDTC treatment effectively reduced the incidence of SANFH. Therefore, the excessive activation of TLR4/NF-?B may interactively suppress the Wnt/?-catenin pathway and induce SANFH. Hence, we propose NF-?B-targeted treatment as a novel therapeutic strategy for SANFH.

| S-EPMC5607349 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data