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The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia

ABSTRACT: The NF-κB pathway is a critical regulator of the immune system and has been implicated in cellular transformation and tumorigenesis. NF-κB response is regulated by the activation state of the IκB kinase (IKK) complex and triggered by a wide spectrum of stimuli. We previously reported that NF-κB is downstream of Notch1 in T cell acute lymphoblastic leukaemia (T-ALL), however both the mechanisms involving Notch1-induced NF-κB activation and the potential importance of NF-κB in the maintenance of the disease are unknown. Here we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models of this type of leukemia. We show that it is not Notch1 itself but Hes1, a canonical Notch target, the responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by a direct transcriptional repression of the deubiquitinating enzyme CYLD, a well-characterized IKK inhibitor. Consistently, CYLD expression is significantly reduced in primary T-ALL leukemias. Finally, we demonstrate that IKK complex inhibition is a promising option for the targeted therapy of T-ALL as suppression of IKK function affected both the survival of human T-ALL cells in vitro and the maintenance of the disease in vivo. Transcriptional consequences of NF-kB inactivation in human T-ALL1 cell line

ORGANISM(S): Homo sapiens

PROVIDER: GSE20667 | GEO | 2011/05/07

SECONDARY ACCESSION(S): PRJNA124923

REPOSITORIES: GEO

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The Notch/Hes1 pathway sustains NF-M-NM-:B activation through CYLD repression in T cell leukemia

Project description:The NF-M-NM-:B pathway is a critical regulator of the immune system and has been implicated in cellular transformation and tumorigenesis. NF-M-NM-:B response is regulated by the activation state of the IM-NM-:B kinase (IKK) complex and triggered by a wide spectrum of stimuli. We previously reported that NF-M-NM-:B is downstream of Notch1 in T cell acute lymphoblastic leukaemia (T-ALL), however both the mechanisms involving Notch1-induced NF-M-NM-:B activation and the potential importance of NF-M-NM-:B in the maintenance of the disease are unknown. Here we visualize Notch-induced NF-M-NM-:B activation using both human T-ALL cell lines and animal models of this type of leukemia. We show that it is not Notch1 itself but Hes1, a canonical Notch target, the responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by a direct transcriptional repression of the deubiquitinating enzyme CYLD, a well-characterized IKK inhibitor. Consistently, CYLD expression is significantly reduced in primary T-ALL leukemias. Finally, we demonstrate that IKK complex inhibition is a promising option for the targeted therapy of T-ALL as suppression of IKK function affected both the survival of human T-ALL cells in vitro and the maintenance of the disease in vivo. Transcriptional consequences of NF-kB inactivation in human T-ALL1 cell line Twenty samples were analyzed: human T-ALL, CEM, KOPT-K, DND41, HPB-ALL cells lines have been treated at 100uM for 16 hours with control peptide or IKKM-NM-3 Nemo binding domain (NBD) inhibitory peptide, that specifically block the canonical NF-M-NM-:B activity by disrupting the interaction of IKKM-NM-3 to IKKM-NM-2 and IKKM-NM-1

2011-05-07 | E-GEOD-20667 | biostudies-arrayexpress

Targeting the NF-κB signaling pathway in Notch1-induced T cell leukemia

Project description:T cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that the majority of TALL patients carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively-active Notch1 activates the NF-κB pathway transcriptionally and via the IκB kinase (IKK) complex, thereby causing increased expression of multiple well-characterized NF-κB target genes in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-κB pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These studies identify NF-κB as one of the major mediators of NOTCH1-induced transformation and suggest that the NF-κB pathway is a potential target of future targeted therapies of T-ALL. Keywords: gene expression analysis, signaling pathway alteration

2006-12-02 | GSE6396 | GEO

Homo sapiens

Project description:The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia

| PRJNA124923 | ENA

Ubiquitination profile of polarized macrophages

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2020-08-06 | PXD018743 | Pride

ATM-Dependent Phosphorylation of Nemo SQ Motifs is Dispensable for Nemo-Mediated Gene Expression Changes in Response to DNA Double Strand Breaks

Project description:In response to DNA double strand breaks (DSBs), the ATM kinase activates NF-κB factors to stimulate gene expression changes that promote survival and allow time for cells to repair damage. In cell lines, ATM can activate NF-κB transcription factors via two independent, convergent mechanisms. One is ATM-mediated phosphorylation of nuclear NF-κB essential modulator (Nemo) protein, which leads to monoubiquitylation and export of Nemo to the cytoplasm where it engages the IκB kinase (IKK) complex to activate NF-κB. Another is DSB-triggered migration of ATM into the cytoplasm where it promotes monoubiquitylation of Nemo and resulting IKK-mediated activation of NF-κB. ATM has many other functions in the DSB response beyond activation of NF-κB, and Nemo activates NF-κB downstream of diverse stimuli, including developmental or proinflammatory stimuli such as lipopolysaccharides (LPS). To elucidate the in vivo role of DSB-induced, ATM-dependent changes in expression of NF-κB-responsive genes, we generated mice expressing phosphomutant Nemo protein lacking consensus SQ sites for phosphorylation by ATM or related kinases. We demonstrate that these mice are viable/healthy, fertile, and exhibit overall normal B and T lymphocyte development. Moreover, treatment of their B lineage cells with LPS induces normal NF-κB-regulated gene expression changes. Furthermore, in marked contrast to results from a pre-B cell line, primary B lineage cells expressing phosphomutant Nemo treated with the genotoxic drug etoposide induce normal ATM- and Nemo-dependent changes in expression of NF-κB-regulated genes. Our data demonstrate that ATM-dependent phosphorylation of Nemo SQ motifs in vivo is dispensable for DSB-signaled changes in expression of NF-κB-regulated genes.

2024-08-08 | GSE264315 | GEO

T Cell Receptor-Induced NF-kB Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-Mediated Calcium Entry

Project description:T cell activation following antigen binding to the T cell receptor (TCR) involves the mobilization of intracellular calcium (Ca2+) to activate the key transcription factors NFAT and NF-κB. The mechanism of NFAT activation by Ca2+ has been determined; however, the role of Ca2+ in controlling NF-κB signaling is poorly understood and the source of Ca2+ required for NF-κB activation is unknown. We demonstrate that TCR- but not TNF- induced NF-κB signaling upstream of IκB kinase (IKK) activation absolutely requires the influx of extracellular Ca2+ via STIM1-dependent CRAC/Orai channels. We further show that Ca2+ influx controls phosphorylation of the NF-κB protein p65 on Ser536 and that this post- translational modification controls its nuclear localization and transcriptional activation. Notably our data reveal that this role for Ca2+ is entirely separate from its upstream control of IκBα degradation, thereby identifying a novel Ca2+- dependent distal step in TCR-induced NF-κB activation. Finally, we demonstrate that this control of distal signaling occurs via Ca2+-dependent PKCk-mediated phosphorylation of p65. Thus, we establish the source of Ca2+ required for TCR induced NF-kB activation and we define a new distal Ca2+-dependent checkpoint in TCR-induced NF-kB signaling that has broad implications for the control of immune cell development and T cell functional specificity.

2016-01-14 | GSE76804 | GEO

Notch1 enhances NF-κB activation to promote CD133+ Skin Cancer Stem Cells

Project description:Cancer stem-like cells are hypothesized to be the major tumor initiating cell (TIC) population of human cutaneous squamous cell carcinoma (hcSCC), but the molecular alterations underpinning their cellular phenotype remain undefined. Here, a small CD133+CD31-CD45-CD61-CD24- (CD133+) cell population enriched for self-renewing and TIC features was isolated by sorting from primary hcSCC tumors. CD133+ cells show enhanced spheroid formation in vitro and tumor generation in vivo. Gene expression profiling comparing CD133+ with CD133- cells revealed that CD133+ cells expressed enriched stem cell-like and cancer-related gene signatures. Eighty differentially expressed stem cell-related genes were identified in CD133+ cells, where the top pathways include Notch, Notch1-mediated NF-κB, and WNT signaling. Overexpression of growth factor receptors, PI3K/mTOR, and STAT pathway genes and inactivation of genes regulating epigenetic modification of chromatin implicated in cancer were also identified. Verification of these gene signatures was conducted with Nanostring in an independent tumor set. Pharmacologic or genetic modulation of Notch1, IKKα, RELA and RELB modulated NF-κB transactivation, the CD133+ population, and phenotype. Immunofluorescent staining confirmed co-localization of CD133+ and IKKα expression in SCC tumor specimens. Our data support the linkage and importance of non-canonical Notch1 and IKK-mediated NF-κB activation in promoting CD133+ population and TIC phenotype in hcSCC.

2019-07-14 | GSE84588 | GEO

Inhibition of endothelial Notch signaling attenuates inflammation [ChIP-Seq]

Project description:Vascular endothelial cells upregulate the Notch ligand Jagged1 in response to inflammatory activation. Here we show that abrogation of endothelial Notch1 signaling impairs induction of key inflammatory target genes. Accordingly, inducible endothelial-targeted knockout of the canonical Notch transcription factor RBPJ reduces inflammation in a murine model of contact hypersensitivity, while overexpression of constitutive active Notch1 has the opposite effect. We show that the proinflammatory role of Notch1 can be attributed to direct genomic priming of the inflammatory landscape involving crosstalk with NF-κB/RelA and selective activation of enhancers associated with Notch-dependent inflammatory genes. This is the first evidence that canonical Notch signaling supports endothelial activation in response to inflammatory cytokines on the chromatin level.

2018-08-29 | GSE87552 | GEO

Expression data from Hes1 conditional knock-out NOTCH1-induced leukemias

Project description:To formally address the biological activity of Hes1 in vivo, we tested the interaction between oncogenic NOTCH1 and acute Hes1 loss in a retroviral-transduction bone marrow transplantation model of NOTCH-induced T-ALL Forced expression of activated NOTCH1 in this model typically results in full leukemia transformation 5-10 weeks later. We performed microarray gene expression analysis of Hes1 wild type and Hes1-/- NOTCH1 induced leukemias

2015-05-07 | E-GEOD-65863 | biostudies-arrayexpress

HES1 and HES4 have both unique and overlapping roles as downstream mediators of Notch-dependent hematopoietic lineage decisions in human

Project description:In both mouse and human, Notch1 activation is the main initial driver to induce T-cell development in hematopoietic progenitor cells. The initiation of this developmental process coincides with Notch1-dependent repression of differentiation towards other hematopoietic lineages. Although well described in mice, the role of the individual Notch1 target genes during these hematopoietic developmental choices is still unclear in human. Here, we investigated the functional capacity of the Notch1 target genes HES1 and HES4 to modulate human Notch1-dependent hematopoietic lineage decisions. Using well-established in vitro cocultures and RNA sequencing, we show that HES1 acts as a repressor of differentiation by maintaining a quiescent stem cell signature in CD34+ hematopoietic progenitor cells. While HES4 can also inhibit NK and myeloid development like HES1, it acts differently on the T- versus B-cell lineage choice. Surprisingly, HES4 is not capable of repressing B-cell development, the most sensitive hematopoietic lineage with respect to Notch-mediated repression. In contrast to HES1, HES4 promotes initiation of early T-cell development. Overall, we show that the Notch1 target genes HES1 and HES4 display both unique and overlapping functions downstream of Notch during human hematopoietic lineage decisions.

2020-07-27 | GSE130614 | GEO

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