Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

Schwarzer, Rolf; Dörken, Bernd; Jundt, Franziska

doi:10.1038/leu.2011.265

Cited by 77 publications

(59 citation statements)

References 34 publications

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“…The role of alternative NF-kB activation pathway in cancer cells remained unclear. Several reports showed that Notch1 regulated the expression of p52 and RelB (35,36). Because, as far as we know, it is the first report to show the interaction of Notch1 and RelB, these findings may be a novel mechanism for regulation of the alternative NF-kB activation pathway by Notch1.…”

Section: Discussionmentioning

confidence: 87%

Dll4-Fc, an Inhibitor of Dll4-Notch Signaling, Suppresses Liver Metastasis of Small Cell Lung Cancer Cells through the Downregulation of the NF-κB Activity

Kuramoto

Goto

Mitsuhashi

et al. 2012

Molecular Cancer Therapeutics

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Notch signaling regulates cell-fate decisions during development and postnatal life. Little is known, however, about the role of Delta-like-4 (Dll4)-Notch signaling between cancer cells, or how this signaling affects cancer metastasis. We, therefore, assessed the role of Dll4-Notch signaling in cancer metastasis. We generated a soluble Dll4 fused to the IgG1 constant region (Dll4-Fc) that acts as a blocker of Dll4-Notch signaling and introduced it into human small cell lung cancer (SCLC) cell lines expressing either high levels (SBC-3 and H1048) or low levels (SBC-5) of Dll4. The effects of Dll4-Fc on metastasis of SCLC were evaluated using a mouse model. Although Dll4-Fc had no effect on the liver metastasis of SBC-5, the number of liver metastasis inoculated with SBC-3 and H1048 cells expressing Dll4-Fc was significantly lower than that injected with control cells. To study the molecular mechanisms of the effects of Dll4-Fc on liver metastasis, a PCR array analysis was conducted. Because the expression of NF-kB target genes was affected by Dll4-Fc, we conducted an electrophoretic mobility shift assay and observed that NF-kB activities, both with and without stimulation by TNF-a, were downregulated in Dll4-Fc-overexpressing SBC-3 and H1048 cells compared with control cells. Moreover, Dll4-Fc attenuates, at least in part, the classical and alternative NF-kB activation pathway by reducing Notch1 signaling. These results suggest that Dll4-Notch signaling in cancer cells plays a critical role in liver metastasis of SCLC by regulating NF-kB signaling.

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Section: Discussionmentioning

confidence: 87%

Dll4-Fc, an Inhibitor of Dll4-Notch Signaling, Suppresses Liver Metastasis of Small Cell Lung Cancer Cells through the Downregulation of the NF-κB Activity

Kuramoto

Goto

Mitsuhashi

et al. 2012

Molecular Cancer Therapeutics

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“…Notch dimerization leads to strong proliferation and apoptosis resistance [48]. Recently, Notch signaling was also showed to be an upstream regulator of NF-kB [49], providing a cross-link between these two pathways.…”

Section: Dysregulated Signaling Pathwaysmentioning

confidence: 99%

Immunologic pathomechanism of Hodgkin's lymphoma

Jóna

Szodoray

Illés

2013

Experimental Hematology

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“…HCMV infection downregulates Notch1, NICD1, and Jag1 proteins. HCMV is known to manipulate NF-B and epithelial growth factor receptor (EGFR) signaling pathways for efficient entry and replication (37,38), and both pathways have cross talk with the Notch signaling pathway (39,40). To determine whether HCMV infection alters Notch pathway protein levels, NPCs were mock or virus infected at an MOI of 3 and Notch1, NICD1, and Jag1 were detected by Western blotting.…”

Section: Hcmv Infection Inhibits Transcription Of Notch1 and Jag1mentioning

confidence: 99%

Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells

Liu

Yang

et al. 2015

J Virol

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Human cytomegalovirus (HCMV) infection of the developing fetus frequently results in major neural developmental damage. In previous studies, HCMV was shown to downregulate neural progenitor/stem cell (NPC) markers and induce abnormal differentiation. As Notch signaling plays a vital role in the maintenance of stem cell status and is a switch that governs NPC differentiation, the effect of HCMV infection on the Notch signaling pathway in NPCs was investigated. HCMV downregulated mRNA levels of Notch1 and its ligand, Jag1, and reduced protein levels and altered the intracellular localization of Jag1 and the intracellular effector form of Notch1, NICD1. These effects required HCMV gene expression and appeared to be mediated through enhanced proteasomal degradation. Transient expression of the viral tegument proteins of pp71 and UL26 reduced NICD1 and Jag1 protein levels endogenously and exogenously. Given the critical role of Notch signaling in NPC growth and differentiation, these findings reveal important mechanisms by which HCMV disturbs neural cell development in vitro. Similar events in vivo may be associated with HCMV-mediated neuropathogenesis during congenital infection in the fetal brain. IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the leading cause of birth defects that primarily manifest as neurological disabilities. Neural progenitor cells (NPCs), key players in fetal brain development, are the most susceptible cell type for HCMV infection in the fetal brain. Studies have shown that NPCs are fully permissive for HCMV infection, which causes neural cell loss and premature differentiation, thereby perturbing NPC fate. Elucidation of virus-host interactions that govern NPC proliferation and differentiation is critical to understanding neuropathogenesis. The Notch signaling pathway is critical for maintaining stem cell status and functions as a switch for differentiation of NPCs. Our investigation into the impact of HCMV infection on this pathway revealed that HCMV dysregulates Notch signaling by altering expression of the Notch ligand Jag1, Notch1, and its active effector in NPCs. These results suggest a mechanism for the neuropathogenesis induced by HCMV infection that includes altered NPC differentiation and proliferation.

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Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

Cited by 77 publications

References 34 publications

Dll4-Fc, an Inhibitor of Dll4-Notch Signaling, Suppresses Liver Metastasis of Small Cell Lung Cancer Cells through the Downregulation of the NF-κB Activity

Dll4-Fc, an Inhibitor of Dll4-Notch Signaling, Suppresses Liver Metastasis of Small Cell Lung Cancer Cells through the Downregulation of the NF-κB Activity

Immunologic pathomechanism of Hodgkin's lymphoma

Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells

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