Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CD95/Fas suppresses NF-B activation through recruitment of KPC2 in a CD95L/FasL-independent mechanism

ABSTRACT: CD95 expression is preserved in triple-negative breast cancers (TNBCs) and CD95 loss in these cells triggers the induction of a pro-inflammatory program promoting the recruitment of cytotoxic NK cells impairing tumor growth. Herein, we identify a novel interaction partner of CD95, Kip1 ubiquitination-promoting complex protein 2 (KPC2) using an unbiased proteomic approach. Independently of CD95L, CD95/KPC2 interaction contributes to the partial degradation of p105 (NFκB1) and the subsequent generation of p50 homodimers, which transcriptionally represses NF-κB-driven gene expression. Mechanistically, KPC2 interacts with the C-terminal region of CD95 and serves as an adaptor to recruit RelA (p65) and KPC1, which acts as E3 ubiquitin-protein ligase promoting the degradation of p105 into p50. Loss of CD95 in TNBC cells releases KPC2, limiting the formation of the NF-κB inhibitory homodimer complex (p50/p50), promoting NF-κB activation and the production of pro-inflammatory cytokines, that could account for the immune landscape remodeling in TNBC cells

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Breast Cancer

SUBMITTER: Luc Negroni

LAB HEAD: Patrick Legembre

PROVIDER: PXD027196 | Pride | 2021-12-06

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	171128_PL_band01_rep1.msf	Msf
	171128_PL_band01_rep1.raw	Raw
	171128_PL_band01_rep2.msf	Msf
	171128_PL_band01_rep2.raw	Raw
	171128_PL_band01_rep3.msf	Msf

Items per page:

1 - 5 of 31

Similar Datasets

CD95 expression in triple negative breast cancer blocks induction of an inflammatory state through differential regulation of NF-κB Signaling [4T1]

Project description:CD95L is expressed by tumor-infiltrating lymphocytes to eliminate CD95-expressing tumor cells and thereby CD95 loss by tumor cells is often considered as a consequence of an immunoediting process. Nonetheless CD95 expression is maintained in most triple negative breast cancers (TNBCs), and we recently reported that CD95 loss in TNBC cells triggers the induction of a pro-inflammatory program promoting the recruitment of cytotoxic NK and CD8+ T-cells and impairing tumor growth. Using a comprehensive proteomic approach, we have identified two yet unknown CD95 interaction partners, Kip1 ubiquitination-promoting complex protein 2 (KPC2) and p65. KPC2 contributes to the partial degradation of p105 (NFκB1) and the subsequent generation of p50 homodimers, which transcriptionally represses pro-inflammatory NF-κB-driven gene expression. Mechanistically, KPC2 directly interacts with the C-terminal region of CD95 and links the receptor to RelA (p65) and KPC1, the catalytic subunit of the KPC complex that acts as E3 ubiquitin-protein ligase promoting the partial degradation of p105 into p50. Loss of CD95 in TNBC cells releases KPC2, limiting the formation of the NF-κB inhibitory homodimer complex (p50/p50), promoting NF-κB activation and the production of pro-inflammatory cytokines including CSF1, CSF2, CXCL1 and IL1 members, known to promote recruitment and differentiation of certain adaptive and innate immune effector cells.

2021-04-17 | GSE172183 | GEO

CD95 expression in triple negative breast cancer blocks induction of an inflammatory state through differential regulation of NF-κB Signaling [MDA-MB-231]

2021-04-17 | GSE172214 | GEO

Miz1 Limits Tumor-promoting Function of Hepatocyte NF-κB independently of Its Transcriptional Activity in Chemical Hepatocarcinogenesis

Project description:NF-κB has a crucial tumor-suppression role in chemical hepatocarcinogenesis (HCC) by preventing hepatocyte apoptosis-induced compensatory proliferation. However, NF-κB is typically activated in chemical HCC animal models and in ~40% HCC patients, in which its role in tumor progression is largely not known. Here we report that transcription factor Miz1 limits tumor-promoting function of NF-κB independently of its transcriptional activity in chemical HCC. In a murine model, hepatocyte-specific deletion of Miz1 exacerbates HCC progression. Miz1 loss results in a unique sub-group of hepatocytes with upregulated NF-κB activity and pro-inflammatory cytokine production, skewing infiltrating macrophages toward M1-like pro-inflammatory phenotype. Mechanistically, Miz1 sequestrates and prevents IKK-phosphorylation of Metadherin (MTDH), thereby inhibiting NF-κB nuclear translocation and transcription activity. In HCC patient specimens, Miz1 expression is inversely correlated with phosphorylation of RelA and MTDH, and poor prognosis. Thus, Miz1 preventing hepatocytes from promoting infiltrating macrophage M1-like phenotype and inflammation in chemical HCC progression.

2021-07-13 | GSE142868 | GEO

Multi-species RELA ChIP-seq of mammalian aortic endothelial cells before and after TNFα stimulation

Project description:TNFα has an evolutionary conserved role in mediating inflammation via activation of the transcription factor NF-κB. The functions of individual NF-κB binding sites are not well understood. To identify conserved and functionally important NF-κB binding sites in mammals, we performed ChIP-seq to map the genome-wide binding of RELA and select histone modifications in primary vascular endothelial cells (ECs) isolated from the aortas of human (HAEC), mouse (MAEC) and cow (BAEC), before and after TNFα. The conserved RELA binding sites show strong epigenetic changes in response to TNFα and enrich near genes controlling vascular development and pro-inflammatory responses. Our method identifies novel modes of RELA-chromatin interactions that are conserved in mammals and shared between multiple cell-types. Particularly, genomic regions bound by RELA prior to stimulation are important responders during TNFα stimulation. We use CRISPR/Cas9 genome editing to validate the roles of the conserved RELA pre-bound sites near pro-inflammatory genes such as CCL2 and PLK2. Our evolutionary approach describes new aspects of mammalian NF-κB biology including its role within super-enhancers and relevance in inflammatory disorders.

2020-10-03 | E-MTAB-7889 | biostudies-arrayexpress

Eugenol modulates the NOD1- NF-κB signaling pathway via targeting NF-κB protein in triple breast cancer cells

Project description:Background: The most aggressive subtype of breast cancer, triple-negative breast cancer (TNBC), has a worse prognosis and a higher probability of relapse since there is a narrow range of treatment options. Identifying and testing potential therapeutic targets for the treatment of TNBC is of high priority. Methods: Using a transcriptional signature of triple-negative breast cancer collected from Gene Expression Omnibus (GEO), CMap was utilized to reposition compounds for the treatment of TNBC. CCK8 and colony formation experiments were performed to detect the effect of the candidate drug on the proliferation of TNBC cells, while flow cytometry was used to detect cell apoptosis. Meanwhile, transwell assay was implemented to detect cell metastasis change caused by the candidate drug. Moreover, the proteomic approach was presently ongoing to evaluate the underlying mechanism of the candidate drug in TNBC. Furthermore, drug affinity responsive target stability (DARTS) coupled with LC-MS/MS was carried out to explore the potential drug target candidate in TNBC cells. Results: We found that the most widely used medication, eugenol, reduced the growth and metastasis of TNBC cells. According to the underlying mechanism revealed by proteomics, eugenol could inhibit TNBC cell proliferation via the NOD1-NF-κB signaling pathway. DARTS experiment further revealed that eugenol may bind to NF-κB in TNBC cells. Concludes: Our findings pointed out that eugenol was a potential candidate drug for the treatment of TNBC.

2023-05-10 | PXD039305 | Pride

PML regulates NF-κB transcriptional activity

Project description:The transcription factor NF-κB is the master regulator of the immune response but also regulates gene expression to influences cell survival, proliferation and differentiation. Inducible site-specific phosphorylation of NF-κB is critical for its activity and appears to be important in gene specific transcriptional control. Promyelocytic Leukemia (PML) is a nuclear protein that forms sub-nuclear structures termed nuclear bodies associated with transcriptionally active genomic regions. We demonstrate that PML promotes NF-κB- induced transcriptional responses by promoting the phosphorylation of NF-κB p65 at key regulatory sites. Our findings demonstrate a critical role for PML in promoting NF-κB transcriptional activity through signal induced post-translational modifications.

2016-06-01 | GSE47828 | GEO

An EZH2-NF-kB Regulatory Axis Drives Expression of Pro-Oncogenic Genetic Signatures in TNBC

Project description:EZH2 has been studied most extensively in the context of PRC2-dependent gene repression. Paradoxically, accumulating evidence indicates non-canonical functions for EZH2 in cancer contexts including promoting gene expression in triple negative breast cancer (TNBC) cells through interactions with the transcription factor NF-kB. We define a genomic profile of EZH2 and NF-kB factor RelA, RelB, and NFKB2/p52 co-localization and positive regulation of a subset of NF-kB targets and genes associated with oncogenic functions in TNBC, which is enriched in patient datasets. We demonstrate interaction between EZH2 and RelA requiring the recently identified EZH2 transactivation domain (TAD), which mediates EZH2 recruitment to and activation of certain NF-kB-dependent genes, and supports downstream stemness phenotypes in TNBC cells. Interestingly, EZH2-NF-kB positive regulation of genes and stemness does not require PRC2. This study provides new insight into pro-oncogenic regulatory functions for EZH2 in breast cancer through PRC2-independent, and NF-kB-dependent regulatory mechanisms.

2023-07-10 | GSE223959 | GEO

A single Thr505 phospho-site mutation reveals an important role for the RelA NF-κB subunit in liver regeneration and cancer

Project description:Post-translational modification of NF-κB subunits provides a mechanism to differentially regulate their activity in response to the many stimuli that can induce this pathway. However, the physiological significance of these modifications is largely unknown and it remains unclear if these have a critical role in the normal and pathological functions of NF-κB in vivo. Among these, phosphorylation of the RelA(p65) Thr505 residue has been described as an important regulator of NF-κB activity in cell lines but its physiological significance was not known. Therefore, to learn more about the role of this pathway in vivo, we generated a knockin mouse with a RelA T505A mutation. Unlike RelA knockout mice, the RelA T505A mice develop normally but exhibit aberrant hepatocyte proliferation following liver partial hepatectomy or damage resulting from carbon tetrachloride treatment. Consistent with these effects, RelA T505A mice exhibit earlier onset of cancer in the N-nitrosodiethylamine (DEN) model of hepatocellular carcinoma. This data reveals a critical pathway controlling NF-κB function in the liver that acts to suppress tumour-promoting activities of RelA.

2015-11-30 | E-MTAB-3596 | biostudies-arrayexpress

Protein Kinase D drives the secretion of invasion mediators in triple negative breast cancer cell lines

Project description:Protein kinase D (PKD) regulates protein secretion at the Golgi complex and has been found to have a pro-oncogenic role in triple-negative breast cancer (TNBC). PKD was previously reported to regulate the secretion of tumor-promoting factors in prostate and pancreatic cancer. Whether PKD plays a similar role in TNBC remains unknown. Here, we used mass spectrometry-based proteomics to characterize the secreted proteome collected from the TNBC cell lines MDA-MB-231 and MDA-MB-468 following pharmacological PKD2 and PKD3 inhibition. Analysis of secretome signatures of response revealed several extracellular matrix related proteins decreased upon PKD inhibition. Amongst the downregulated proteins were previously described TNBC invasion mediators, such as TNC, STC-1, LIF, MMP-1 and M-CSF. The secretion of these proteins, as well as of MMP-13, IL-11 and GM-CSF, was further validated by multiplex assays to be regulated by PKD. Secretion regulation of this protein set by PKD was more evident in TNBC metastatic cell lines than in primary tumor-derived. Individual knockdown of PKD2 and PKD3 revealed that secretion of this protein set is predominantly PKD2-driven in MDA-MB-231 cells. This study improves the current understanding of PKD’s contribution to TNBC secretion and uncovers a novel function of PKD2 in the release of a pro-invasive secretome. / This study improves the current understanding of PKD’s contribution to TNBC secretion and uncovers the distinct pro-invasive substrates of PKD2 and PKD3.

2024-01-17 | PXD041042 | Pride

An autoregulatory RelB:p50 NF-κB pathway perpetuates pro-survival TNF response in multiple myeloma

Project description:Pro-inflammatory cytokines were shown to promote growth and survival of cancerous cells. TNF induced RelA:p50 NF-κB dimer via the canonical pathway is thought to link inflammation with cancer. Integrating biochemical and computational studies we identify that deficiency of non-canonical signal transducer p100 triggers a positive autoregulatory loop, which instead perpetuates an alternate RelB:p50 containing NF-κB activity upon TNF treatment. TNF stimulated RelB:p50 dimer is sufficient for mediating NF-κB target gene-expressions and suppressing apoptotic cellular death independent of principal NF-κB subunit RelA. We further demonstrate that activating mutations in non-canonical NF-κB module deplete multiple myeloma cells of p100, thereby, provoking autoregulatory RelB:p50 activation. Finally, autoregulatory control reinforces protracted pro-survival NF-κB response, albeit comprising of RelB:p50, upon TNF priming that protects myeloma cells with dysfunctional p100 from subsequent apoptotic insults. In sum, we present evidence for positive autoregulation mediated through the NF-κB system and its potential involvement in human neoplasm.

2017-06-12 | GSE68615 | GEO

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