scholarly journals MarvelD3 couples tight junctions to the MEKK1–JNK pathway to regulate cell behavior and survival

2014 ◽  
Vol 204 (5) ◽  
pp. 821-838 ◽  
Author(s):  
Emily Steed ◽  
Ahmed Elbediwy ◽  
Barbara Vacca ◽  
Sébastien Dupasquier ◽  
Sandra A. Hemkemeyer ◽  
...  
Keyword(s):  
Tight Junctions ◽  
Tumor Cell Line ◽  
Metastatic Tumor ◽  
Tumor Formation ◽  
Cell Behavior ◽  
Permeability Barrier ◽  
Jnk Pathway ◽  
Junctional Permeability ◽  
Jnk Activation

MarvelD3 is a transmembrane component of tight junctions, but there is little evidence for a direct involvement in the junctional permeability barrier. Tight junctions also regulate signaling mechanisms that guide cell proliferation; however, the transmembrane components that link the junction to such signaling pathways are not well understood. In this paper, we show that MarvelD3 is a dynamic junctional regulator of the MEKK1–c-Jun NH2-terminal kinase (JNK) pathway. Loss of MarvelD3 expression in differentiating Caco-2 cells resulted in increased cell migration and proliferation, whereas reexpression in a metastatic tumor cell line inhibited migration, proliferation, and in vivo tumor formation. Expression levels of MarvelD3 inversely correlated with JNK activity, as MarvelD3 recruited MEKK1 to junctions, leading to down-regulation of JNK phosphorylation and inhibition of JNK-regulated transcriptional mechanisms. Interplay between MarvelD3 internalization and JNK activation tuned activation of MEKK1 during osmotic stress, leading to junction dissociation and cell death in MarvelD3-depleted cells. MarvelD3 thus couples tight junctions to the MEKK1–JNK pathway to regulate cell behavior and survival.

scholarly journals Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

2015 ◽  
Vol 112 (52) ◽  
pp. E7230-E7238 ◽  
Author(s):  
Nathalie Knies ◽  
Begüm Alankus ◽  
Andre Weilemann ◽  
Alexandar Tzankov ◽  
Kristina Brunner ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Jnk Pathway ◽  
Large B Cell Lymphoma ◽  
Jnk Inhibitors ◽  
Jnk Activation ◽  
Large B Cell

The aggressive activated B cell-like subtype of diffuse large B-cell lymphoma is characterized by aberrant B-cell receptor (BCR) signaling and constitutive nuclear factor kappa-B (NF-κB) activation, which is required for tumor cell survival. BCR-induced NF-κB activation requires caspase recruitment domain-containing protein 11 (CARD11), and CARD11 gain-of-function mutations are recurrently detected in human diffuse large B-cell lymphoma (DLBCL). To investigate the consequences of dysregulated CARD11 signaling in vivo, we generated mice that conditionally express the human DLBCL-derived CARD11(L225LI) mutant. Surprisingly, CARD11(L225LI) was sufficient to trigger aggressive B-cell lymphoproliferation, leading to early postnatal lethality. CARD11(L225LI) constitutively associated with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) to simultaneously activate the NF-κB and c-Jun N-terminal kinase (JNK) signaling cascades. Genetic deficiencies of either BCL10 or MALT1 completely rescued the phenotype, and pharmacological inhibition of JNK was, similar to NF-κB blockage, toxic to autonomously proliferating CARD11(L225LI)-expressing B cells. Moreover, constitutive JNK activity was observed in primary human activated B cell-like (ABC)-DLBCL specimens, and human ABC-DLBCL cells were also sensitive to JNK inhibitors. Thus, our results demonstrate that enforced activation of CARD11/BCL10/MALT1 signaling is sufficient to drive transformed B-cell expansion in vivo and identify the JNK pathway as a therapeutic target for ABC-DLBCL.

scholarly journals Loss offlflTriggers JNK-Dependent Cell Death inDrosophila

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Jiuhong Huang ◽  
Lei Xue
Keyword(s):  
Cell Death ◽  
Function Analysis ◽  
Ectopic Expression ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Jnk Pathway ◽  
Dependent Cell ◽  
Jnk Activation ◽  
First Time

falafel(flfl) encodes aDrosophilahomolog of human SMEK whosein vivofunctions remain elusive. In this study, we performed gain-of-function and loss-of-function analysis inDrosophilaand identified flfl as a negative regulator of JNK pathway-mediated cell death. While ectopic expression offlflsuppresses TNF-triggered JNK-dependent cell death, loss offlflpromotes JNK activation and cell death in the developing eye and wing. These data report for the first time an essential physiological function offlflin maintaining tissue homeostasis and organ development. As the JNK signaling pathway has been evolutionary conserved from fly to human, a similar role of PP4R3 in JNK-mediated physiological process is speculated.

Platelet decoys inhibit thrombosis and prevent metastatic tumor formation in preclinical models

2019 ◽  
Vol 11 (479) ◽  
pp. eaau5898 ◽  
Author(s):  
Anne-Laure Papa ◽  
Amanda Jiang ◽  
Netanel Korin ◽  
Michelle B. Chen ◽  
Erin T. Langan ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Rabbit Model ◽  
Cell Aggregation ◽  
Metastatic Tumor ◽  
Arterial Injury ◽  
Tumor Formation ◽  
Cell Arrest ◽  
Normal Hemostasis

Platelets are crucial for normal hemostasis; however, their hyperactivation also contributes to many potentially lethal pathologies including myocardial infarction, stroke, and cancer. We hypothesized that modified platelets lacking their aggregation and activation capacity could act as reversible inhibitors of platelet activation cascades. Here, we describe the development of detergent-extracted human modified platelets (platelet decoys) that retained platelet binding functions but were incapable of functional activation and aggregation. Platelet decoys inhibited aggregation and adhesion of platelets on thrombogenic surfaces in vitro, which could be immediately reversed by the addition of normal platelets; in vivo in a rabbit model, pretreatment with platelet decoys inhibited arterial injury–induced thromboembolism. Decoys also interfered with platelet-mediated human breast cancer cell aggregation, and their presence decreased cancer cell arrest and extravasation in a microfluidic human microvasculature on a chip. In a mouse model of metastasis, simultaneous injection of the platelet decoys with tumor cells inhibited metastatic tumor growth. Thus, our results suggest that platelet decoys might represent an effective strategy for obtaining antithrombotic and antimetastatic effects.

Suppression of tumorigenicity in Wilms tumor by the p15.5-p14 region of chromosome 11

Science ◽  
1991 ◽  
Vol 254 (5029) ◽  
pp. 293-295
Author(s):  
SF Dowdy ◽  
CL Fasching ◽  
D Araujo ◽  
KM Lai ◽  
E Livanos ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Line ◽  
Nude Mice ◽  
Wilms Tumor ◽  
Genetic Locus ◽  
Tumor Cell Line ◽  
Tumor Formation ◽  
The Other ◽  
Chromosome 11

Wilms tumor has been associated with genomic alterations at both the 11p13 and 11p15 regions. To differentiate between the involvement of these two loci, a chromosome 11 was constructed that had one or the other region deleted, and this chromosome was introduced into the tumorigenic Wilms tumor cell line G401. When assayed for tumor-forming activity in nude mice, the 11p13-deleted, but not the 11p15.5-p14.1-deleted chromosome, retained its ability to suppress tumor formation. These results provide in vivo functional evidence for the existence of a second genetic locus (WT2) involved in suppressing the tumorigenic phenotype of Wilms tumor.

scholarly journals Zebrafish-Based Screening Models for the Identification of Anti-Metastatic Drugs

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2407
Author(s):  
Joji Nakayama ◽  
Hideki Makinoshima
Keyword(s):  
Animal Model ◽  
Drug Discovery ◽  
Cancer Cells ◽  
High Throughput Screening ◽  
Metastatic Tumor ◽  
Tumor Formation ◽  
Zebrafish Model ◽  
Step Process ◽  
Physiological Relevance

Metastasis, a leading contributor to the morbidity of cancer patients, occurs through a multi-step process: invasion, intravasation, extravasation, colonization, and metastatic tumor formation. Each process is not only promoted by cancer cells themselves but is also affected by their microenvironment. Given this complexity, drug discovery for anti-metastatic drugs must consider the interaction between cancer cells and their microenvironments. The zebrafish is a suitable vertebrate animal model for in vivo high-throughput screening studies with physiological relevance to humans. This review covers the zebrafish model used to identify anti-metastatic drugs.

scholarly journals 1-Naphthylisothiocyanate-induced permeability of hepatic tight junctions to proteins

1986 ◽  
Vol 238 (2) ◽  
pp. 323-328 ◽  
Author(s):  
K S Kan ◽  
R Coleman
Keyword(s):  
Tight Junctions ◽  
Bile Flow ◽  
Gamma Globulin ◽  
Oxidase Inhibitor ◽  
Permeability Barrier ◽  
Permeability Change ◽  
Bile Sample ◽  
Small Peak ◽  
Early Action ◽  
Junctional Permeability

We have studied the early action of 1-naphthylisothiocyanate (ANIT) in relation to its effect on the permeability barrier formed by hepatic tight junctions. Materials having different Mr values [inulin (5000), horseradish peroxidase (HRP) (40,000), ovalbumin (also 40,000) and pig gamma-globulin (IgG) (160,000)] were individually pulsed, within 1 min, into perfused rat livers operating under single-pass conditions. In untreated rats, a small peak of HRP and ovalbumin and a comparatively larger peak of inulin were observed in the bile at 7 min. In rats treated with ANIT, with increasing duration of ANIT treatment the inulin peak increased proportionally, whereas the HRP and ovalbumin peaks remained unchanged until after 10 h of ANIT exposure; gamma-globulin was not detected in the 7 min bile sample until after 14 h of ANIT treatment. Bile flow in all rats remained approximately the same until after 14 h of ANIT pretreatment, when substantial bile-flow reduction was observed. Phenobarbitone pretreatment increased the effect of ANIT and massively elevated the first HRP peak; it also shortened the time (to 4 h) at which the increase in permeability to this protein was observed. In contrast, the first HRP peak was virtually abolished in rats that had received the mixed-function-oxidase inhibitor SKF 525A. These experiments suggest that (i) ANIT progressively increased the permeability of the junctional barrier before the reduction in bile flow, (ii) the ANIT-increased permeability change seems to be inversely dependent upon the Mr of the infused proteins, and (iii) metabolites of ANIT were involved in the development of the junctional permeability change.

scholarly journals Protein Phosphatase 4 Promotes Hepatocyte Lipoapoptosis by Regulating RAC1/MLK3/JNK Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Xiuqing Huang ◽  
Guang Yang ◽  
Li Zhao ◽  
Huiping Yuan ◽  
Hao Chen ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Hepatic Insulin Resistance ◽  
Jnk Pathway ◽  
Pathway Activation ◽  
Jnk Signaling Pathway ◽  
Induced Apoptosis ◽  
Jnk Activation ◽  
First Time

Lipotoxicity-induced apoptosis, also referred to as lipoapoptosis, is one of the important initial factors promoting the progression from hepatosteatosis to nonalcoholic steatohepatitis (NASH). Saturated free fatty acids (SFAs), which are increased significantly in NASH, are directly hepatotoxic which induce hepatocyte lipoapoptosis. Previously, we reported that protein phosphatase 4 (PP4) was a novel regulator of hepatic insulin resistance and lipid metabolism, but its role in hepatic lipoapoptosis remains unexplored. In this study, we found out that PP4 was upregulated in the livers of western diet-fed-induced NASH mice and SFA-treated murine primary hepatocytes and HepG2 cells. In addition, we found for the first time that suppression of PP4 decreased SFA-induced JNK activation and expression of key modulators of hepatocyte lipoapoptosis including p53-upregulated modulator of apoptosis (PUMA) and Bcl-2-interacting mediator (Bim) and reduced hepatocyte lipoapoptosis level as well both in vitro and in vivo. Further study revealed that PP4 induced JNK activation and lipoapoptosis-related protein expression by regulating the RAC1/MLK3 pathway instead of the PERK/CHOP pathway. The effects of palmitate-treated and PP4-induced lipoapoptosis pathway activation were largely abolished by RAC1 inhibition. Moreover, we identified that PP4 interacted with RAC1 and regulated GTPase activity of RAC1. In conclusion, these results demonstrated that PP4 was a novel regulator of hepatocyte lipoapoptosis and mediated hepatocyte lipoapoptosis by regulating the RAC1/MLK3/JNK signaling pathway. Our finding provided new insights into the mechanisms of this process.

scholarly journals Inhibition of JNK activation prolongs survival after smoke inhalation from fires

2007 ◽  
Vol 292 (4) ◽  
pp. L984-L991 ◽  
Author(s):  
Olga L. Syrkina ◽  
Deborah A. Quinn ◽  
Walter Jung ◽  
Bin Ouyang ◽  
Charles A. Hales
Keyword(s):  
Lung Injury ◽  
Critical Role ◽  
Inflammatory Cells ◽  
Smoke Inhalation ◽  
Sprague Dawley ◽  
Jnk Pathway ◽  
Initial Injury ◽  
Acute Inflammatory Cell ◽  
Jnk Activation

Initial injury from smoke inhalation is mainly to the trachea and bronchi and is characterized by mucosal hyperemia and increased microvascular permeability, exfoliation of epithelial lining, mucous secretion, mucous plugging, and an acute inflammatory cell influx. In this study, we explore the role of the c-Jun N-terminal protein kinase (JNK) pathway in smoke inhalation lung injury using a rat model of exposure to smoke from burning cotton. Male Sprague-Dawley rats were exposed to smoke from burning cotton for 15 min, and 1 h after injury a JNK inhibitor (SP-600125) or vehicle was injected. We measured neutrophil influx, cytokine release, percent of apoptotic cells, airway plugging, and survival. Administration of a JNK inhibitor 1 h after smoke inhalation decreased airway apoptosis, mucous plugging, influx of inflammatory cells, and the release of cytokines and significantly prolonged animal survival ( P < 0.05). These in vivo data show that the JNK pathway plays a critical role in smoke-induced lung injury and offer an attractive therapeutic approach for this injury.

scholarly journals Distinct effects of two CD44 isoforms on tumor growth in vivo.

1991 ◽  
Vol 174 (4) ◽  
pp. 859-866 ◽  
Author(s):  
M S Sy ◽  
Y J Guo ◽  
I Stamenkovic
Keyword(s):  
Tumor Growth ◽  
B Cell Lymphoma ◽  
Metastatic Tumor ◽  
Tumor Formation ◽  
Surface Glycoprotein ◽  
Cdna Clones ◽  
Lymphoma Cells ◽  
Cell Surface Glycoprotein ◽  
Cd44 Isoforms

Tumor growth is dependent in part on interactions between tumor cells and the extracellular matrix of host tissues. Expression of the cell surface glycoprotein CD44/Pgp-1, which mediates cell-substrate interactions is increased in many types of malignancies, but the role of CD44 in tumor growth is largely undefined. Recently, two isoforms of CD44 have been identified: an 80-90 kD form, which has high affinity for cell bound hyaluronate and a 150 kD form which does not mediate attachment to hyaluronate-coated surfaces. In this work, human B cell lymphoma cells stably transfected with cDNA clones encoding either of the two CD44 isoforms were compared for tumorigenicity and metastatic potential in nude mice. Expression of the 80-90 kD form but not the 150 kD form of CD44 greatly enhanced both local tumor formation and metastatic proclivity of the lymphoma cells. Our results suggest that CD44 polypeptides may play an important role in regulating primary and metastatic tumor development in vivo.

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