Browse
Submit Data
Databases
API
Help

Dataset Information

7 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL.

ABSTRACT: In chronic lymphocytic leukemia (CLL), the lymph node (LN) microenvironment delivers critical survival signals by inducing the expression of anti-apoptotic Bcl-2 members Bcl-XL, Bfl-1, and Mcl-1, resulting in apoptosis blockade. We determined previously that resistance against various drugs, among which is the clinically applied BH3 mimetic venetoclax, is dominated by upregulation of the anti-apoptotic regulator Bcl-XL. Direct clinical targeting of Bcl-XL by, e.g., Navitoclax is however not desirable due to induction of thrombocytopenia. Since the actual regulation of Bcl-XL in CLL in the context of the LN microenvironment is not well elucidated, we investigated various candidate LN signals to drive Bcl-XL expression. We found a dominance for NF-κB signaling upon CD40 stimulation, which results in activation of both the canonical and non-canonical NF-κB signaling pathways. We demonstrate that expression of Bcl-XL is first induced by the canonical NF-κB pathway, and subsequently boosted and continued via non-canonical NF-κB signaling through stabilization of NIK. NF-κB subunits p65 and p52 can both bind to the Bcl-XL promoter and activate transcription upon CD40 stimulation. Moreover, canonical NF-κB signaling was correlated with Bfl-1 expression, whereas Mcl-1 in contrast, was not transcriptionally regulated by NF-κB. Finally, we applied a novel compound targeting NIK to selectively inhibit the non-canonical NF-κB pathway and showed that venetoclax-resistant CLL cells were sensitized to venetoclax. In conclusion, protective signals from the CLL microenvironment can be tipped towards apoptosis sensitivity by interfering with non-canonical NF-κB signaling.

SUBMITTER: Haselager M

PROVIDER: S-EPMC8167103 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

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

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage.

Project description:Nuclear factor kappa B (NF-κB) promotes cell survival in response to genotoxic stress by inducing the expression of anti-apoptotic proteins including Bcl-xL, which protects mitochondria from stress-induced mitochondrial outer membrane permeabilization (MOMP). Here we show that the multifunctional sorting protein Pacs-2 (phosphofurin acidic cluster sorting protein-2) is required for Bcl-xL induction following DNA damage in primary mouse thymocytes. Consequently, in response to DNA damage, Pacs-2(-/-) thymocytes exhibit a blunted induction of Bcl-xL, increased MOMP and accelerated apoptosis. Biochemical studies show that cytoplasmic PACS-2 promotes this DNA damage-induced anti-apoptotic pathway by interacting with ataxia telangiectasia mutated (ATM) to drive NF-κB activation and induction of Bcl-xL. However, Pacs-2 was not required for tumor necrosis factor-α-induced NF-κB activation, suggesting a role for PACS-2 selectively in NF-κB activation in response to DNA damage. These findings identify PACS-2 as an in vivo mediator of the ATM and NF-κB-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage.

| S-EPMC5072422 | biostudies-literature

Regulation of apoptosis by an intrinsically disordered region of Bcl-xL.

Project description:Intrinsically disordered regions (IDRs) of proteins often regulate function upon post-translational modification (PTM) through interactions with folded domains. An IDR linking two ?-helices (?1-?2) of the antiapoptotic protein Bcl-xL experiences several PTMs that reduce antiapoptotic activity. Here, we report that PTMs within the ?1-?2 IDR promote its interaction with the folded core of Bcl-xL that inhibits the proapoptotic activity of two types of regulatory targets, BH3-only proteins and p53. This autoregulation utilizes an allosteric pathway whereby, in one direction, the IDR induces a direct displacement of p53 from Bcl-xL coupled to allosteric displacement of simultaneously bound BH3-only partners. This pathway operates in the opposite direction when the BH3-only protein PUMA binds to the BH3 binding groove of Bcl-xL, directly displacing other bound BH3-only proteins, and allosterically remodels the distal site, displacing p53. Our findings show how an IDR enhances functional versatility through PTM-dependent allosteric regulation of a folded protein domain.

| S-EPMC5899648 | biostudies-literature

CD40L Priming of Platelets via NF-κB Activation is CD40- and TAK1-Dependent.

Project description:Background CD40 ligand (CD40L) is a thromboinflammatory molecule that predicts cardiovascular events. CD40L is a strong activator of nuclear factor kappa B (NF-κB) in platelets that primes and enhances platelet activation in response to thrombotic stimuli. In addition to its classical receptor CD40, CD40L binds αIIbβ3, α5β1, and αMβ2 in various cell types. However, the function of the different CD40L receptors on platelets remains unexplored. The present study aims to identify the receptors of CD40L, involved in platelet NF-κB activation, their downstream signaling and their implication in platelet aggregation. Methods and Results We showed that platelets express CD40, αIIbβ3, and α5β1 and release CD40L in response to sCD40L stimulation. sCD40L alone dose-dependently induced platelet NF-κB activation; this effect was absent in CD40-/- mouse platelets and inhibited by the CD40 blockade, but was unaffected by the αIIbβ3 or α5β1 blockade in human platelets. sCD40L/CD40 axis activates transforming growth factor-β-activated kinase 1 upstream of NF-κB. In functional studies, sCD40L alone did not affect platelet aggregation but potentiated the aggregation response in the presence of suboptimal doses of thrombin; this effect was abolished by CD40, transforming growth factor-β-activated kinase 1, and NF-κB inhibitors. Conclusions CD40L primes platelets via signaling pathways involving CD40/transforming growth factor-β-activated kinase 1/NF-κB, which predisposes platelets to enhanced activation and aggregation in response to thrombotic stimuli.

| S-EPMC6405550 | biostudies-other

The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNAInduced Silencing of NF-κB-Inducing Kinase.

Project description:NF-κB signaling through both canonical and non-canonical pathways plays a central role in immune responses and inflammation. NF-κB-inducing kinase (NIK) stabilization is a key step in activation of the non-canonical pathway and its dysregulation implicated in various hematologic malignancies. The tumor suppressor, p53, is an established cellular gatekeeper of proliferation. Abnormalities of the TP53 gene have been detected in more than half of all human cancers. While the non-canonical NF-κB and p53 pathways have been explored for several decades, no studies to date have documented potential cross-talk between these two cancer-related mechanisms. Here, we demonstrate that p53 negatively regulates NIK in an miRNA-dependent manner. Overexpression of p53 decreased the levels of NIK, leading to inhibition of the non-canonical NF-κB pathway. Conversely, its knockdown led to increased levels of NIK, IKKα phosphorylation, and p100 processing. Additionally, miR-34b induced by nutlin-3 directly targeted the coding sequences (CDS) of NIK. Treatment with anti-miR-34b-5p augmented NIK levels and subsequent non-canonical NF-κB signaling. Our collective findings support a novel cross-talk mechanism between non-canonical NF-κB and p53.

| S-EPMC6999715 | biostudies-literature

Expression of ZAP70 in CLL activates NF-κB signalling

Project description:Chronic lymphocytic leukemia (CLL) is a disease with a highly variable prognosis. The clinical course can however be predicted thanks to prognostic markers. Poor prognosis is associated with expression of a B cell receptor (BCR) from unmutated immunoglobulin variable heavy-chain genes (IgVH) and expression of zeta associated protein of 70 kDa (ZAP-70). The reason why ZAP-70 expression is associated with poor prognosis and whether the protein has a direct pathogenic function is at present unknown. By transfer of ZAP-70 to CLL cells, we show here that expression of ZAP-70 in CLL cells leads to increased expression of the NF-κB target genes interleukin-1β (IL-1β), IL-6 and IL-8 upon BCR triggering. This could be blocked by inhibition of NF-κB signaling through inhibition of IκB kinases (IKK). Transcriptome analysis identified a NF-κB RelA signature imposed by ZAP-70 expression in BCR stimulated CLL cells. We conclude that ZAP-70 acts directly as an amplifier of NF-κB signaling in CLL cells which could be an underlying mechanism for its association with poor prognosis and which may represent a therapeutic target.

2013-10-22 | GSE51286 | GEO

Late-phase synthesis of IκBα insulates the TLR4-activated canonical NF-κB pathway from noncanonical NF-κB signaling in macrophages.

Project description:The nuclear factor κB (NF-κB) transcription factors coordinate the inflammatory immune response during microbial infection. Pathogenic substances engage canonical NF-κB signaling through the heterodimer RelA:p50, which is subjected to rapid negative feedback by inhibitor of κBα (IκBα). The noncanonical NF-κB pathway is required for the differentiation of immune cells; however, cross-talk between both pathways can occur. Concomitantly activated noncanonical signaling generates p52 from the p100 precursor. The synthesis of p100 is induced by canonical signaling, leading to the formation of the late-acting RelA:p52 heterodimer. This cross-talk prolongs inflammatory RelA activity in epithelial cells to ensure pathogen clearance. We found that the Toll-like receptor 4 (TLR4)-activated canonical NF-κB signaling pathway is insulated from lymphotoxin β receptor (LTβR)-induced noncanonical signaling in mouse macrophage cell lines. Combined computational and biochemical studies indicated that the extent of NF-κB-responsive expression of Nfkbia, which encodes IκBα, inversely correlated with cross-talk. The Nfkbia promoter showed enhanced responsiveness to NF-κB activation in macrophages compared to that in fibroblasts. We found that this hyperresponsive promoter engaged the RelA:p52 dimer generated during costimulation of macrophages through TLR4 and LTβR to trigger synthesis of IκBα at late time points, which prevented the late-acting RelA cross-talk response. Together, these data suggest that, despite the presence of identical signaling networks in cells of diverse lineages, emergent cross-talk between signaling pathways is subject to cell type-specific regulation. We propose that the insulation of canonical and noncanonical NF-κB pathways limits the deleterious effects of macrophage-mediated inflammation.

| S-EPMC5260935 | biostudies-literature

Context-Specific Regulation of NF-κB Target Gene Expression by EZH2 in Breast Cancers

Project description:Both EZH2 and NF-κB contribute to aggressive breast cancer, yet whether the two oncogenic factors have functional cross-talk in breast cancer is largely unknown. Here, we uncover an unexpected role of EZH2 in conferring the constitutive activation of NF-κB target gene expression in ER-negative basal-like breast cancer cells. This function of EZH2 is independent of its histone methyltransferase activity but requires the physical interaction with RelA/RelB to promote the expression of NF-κB targets. Intriguingly, EZH2 acts oppositely in repressing NF-κB targets in ER-positive luminal-like breast cancer cells by interacting with ER and directing repressive histone methylation. Thus, EZH2 function as a double-facet molecule in breast cancers, functioning either as a transcriptional activator or repressor of NF-κB targets, in a cell context-dependent manner. These findings reveals an additional mechanism by which EZH2 promotes breast cancer progression and also underscore the need for developing context-specific strategy for therapeutic targeting of EZH2 in breast cancers.

2011-08-15 | GSE30670 | GEO

NLRP12 Promotes Mouse Neutrophil Differentiation through Regulation of Non-canonical NF-κB and MAPK<sup>ERK1/2</sup> Signaling.

Project description:Neutrophils are the most important component of the innate immune system. Mechanistic understanding of the mechanism underlying neutrophil differentiation remains elusive. Using genome-wide RNA-seq, we identified genes whose expression is dramatically up-regulated during neutrophil differentiation. Among them is nucleotide-binding leucine-rich repeat and pyrindomain-containing receptor 12 (NLRP12), which plays a role in immune inflammatory responses. Genetic ablation of NLRP12 suppresses NF-κB inducing kinase (NIK) stabilization, RelB nuclear translocation and neutrophil differentiation in vitro. At a mechanistic level, NLRP12 inhibits the activity of mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK1/2), relieves ERK1/2 suppression of NIK protein levels. Thus, NLRP12 enhances noncanonical NF-κB signaling through inhibition of ERK1/2 signaling, thereby promoting neutrophil differentiation.

| S-EPMC5821036 | 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

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