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.

DUSP4 inhibits autophagic cell death in PTC by inhibiting JNK-BCL2-Beclin1 signaling

2021 ◽  
Author(s):  
Huixiang He ◽  
zhenshuang Du ◽  
Jianqing Lin ◽  
Wenyi Wu ◽  
Yihuang Yu
Keyword(s):  
Cell Death ◽  
Specific Inhibitor ◽  
Autophagic Cell Death ◽  
Negative Regulator ◽  
Loss Of Function ◽  
In Vivo Assays ◽  
Prevention And Cure ◽  
The Relationship

DUSP4 is a prognostic marker and potential target of papillary thyroid carcinoma (PTC). However, the molecular mechanism underlying DUSP4-regulated PTC carcinogenesis is unclear. DUSP4 is a negative regulator of the autophagy promoter, JNK. This study aimed to explore the relationship between DUSP4 and JNK-mediated autophagic cell death in PTC. In this study, we explored the roles of DUSP4 in PTC using gain-of-function and loss-of-function assays. In addition, we further identified the significance of JNK-BCL2-Beclin1-autophagy signaling on DUSP4-regulated PTC carcinogenesis by combining DUSP4 silencing with JNK specific inhibitor (SP600125). We found that DUSP4 silencing promoted the phosphorylation of JNK and BCL2 in PTC cells and enhanced the release of Beclin1 from BCL2-Beclin1 complex. DUSP4 silencing promoted autophagy and death in PTC cells.The death and autophagy enhanced by DUSP4 silencing was reversed by JNK inhibitor. We further extended the in vitro experiments by injecting K1 cells transduced with DUSP4-silencing vector subcutaneously into nude mice. In vivo assays showed that DUSP4 silencing not only inhibited tumor growth, but also promoted JNK and BCL2 phosphorylation and LC3II expression.Overall, DUSP4 inhibits BCL2-Beclin1- autophagy signaling through negatively regulating JNK activity, thus inhibiting PTC oncogenesis.This study provides more potential clues for the prevention and cure of PTC.

scholarly journals PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Shuiping Liu ◽  
Haoming Lin ◽  
Da Wang ◽  
Qiang Li ◽  
Hong Luo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Clinical Success ◽  
Dominant Role ◽  
Autophagic Cell Death ◽  
Jnk Activation ◽  
First Time ◽  
The Relationship

Abstract5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 (PCDH17) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between PCDH17 and 5-FU resistance in CRC remains unclear. Here, we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of PCDH17 was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death. Furthermore, autophagy played a dominant role in PCDH17-induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity. Mechanistically, we showed that c-Jun NH2-terminal kinase (JNK) activation was a key determinant in PCDH17-induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells. Taken together, our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.

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 CASK Silence Overcomes Sorafenib Resistance of Hepatocellular Carcinoma Through Activating Apoptosis and Autophagic Cell Death

2021 ◽  
Vol 11 ◽  
Author(s):  
Bisha Ding ◽  
Chang Bao ◽  
Luqi Jin ◽  
Liang Xu ◽  
Weimin Fan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Autophagic Cell Death ◽  
Cell Counting ◽  
Tumor Xenograft ◽  
Confocal Laser ◽  
Loss Of Function ◽  
Jnk Pathway ◽  
Interfering Rna

Hepatocellular carcinoma (HCC) patients usually fail to be treated because of drug resistance, including sorafenib. In this study, the effects of CASK in HCC were investigated using gain- or loss-of-function strategies by performing cell counting kit-8 assay, colony formation assay, flow cytometry, transmission electron microscopy, immunofluorescent confocal laser microscopy, tumor xenograft experiment and immunohistochemistry staining. The current results suggested that CASK expression was positively associated with sorafenib resistance and poor prognosis of HCC. Moreover, inhibition of CASK increased the role of sorafenib partially by promoting apoptosis and autophagy, while CASK overexpression presented the opposite effects. Besides, when treatment with sorafenib, inhibition of apoptosis using the pan-caspase inhibitor Z-VAD-FMK and inhibition of autophagy using autophagy inhibitor 3-Methyladenine (3-MA) or small interfering RNA (siRNA) of LC3B all significantly reversed CASK knockout-induced effects, suggesting that both apoptosis and autophagy were involved in CASK-mediated above functions and autophagy played a pro-death role in this research. Intriguingly, similar results were observed in vivo. In molecular level, CASK knockout activated the c-Jun N-terminal kinase (JNK) pathway, and treatment with JNK inhibitor SP600125 or transiently transfected with siRNA targeting JNK significantly attenuated CASK knockout-mediated autophagic cell death. Collectively, all these results together indicated that CASK might be a promising biomarker and a potential therapeutic target for HCC patients.

scholarly journals The Ral/Exocyst Effector Complex Counters c-Jun N-Terminal Kinase-Dependent Apoptosis in Drosophila melanogaster

2006 ◽  
Vol 26 (23) ◽  
pp. 8953-8963 ◽  
Author(s):  
Maria Balakireva ◽  
Carine Rossé ◽  
Johanna Langevin ◽  
Yu-chen Chien ◽  
Michel Gho ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Map Kinase ◽  
Cell Fate ◽  
P38 Map Kinase ◽  
Negative Regulator ◽  
Jnk Pathway ◽  
Mitogen Activated Protein ◽  
Ral Gtpase ◽  
Jnk Activation

ABSTRACT Ral GTPase activity is a crucial cell-autonomous factor supporting tumor initiation and progression. To decipher pathways impacted by Ral, we have generated null and hypomorph alleles of the Drosophila melanogaster Ral gene. Ral null animals were not viable. Reduced Ral expression in cells of the sensory organ lineage had no effect on cell division but led to postmitotic cell-specific apoptosis. Genetic epistasis and immunofluorescence in differentiating sensory organs suggested that Ral activity suppresses c-Jun N-terminal kinase (JNK) activation and induces p38 mitogen-activated protein (MAP) kinase activation. HPK1/GCK-like kinase (HGK), a MAP kinase kinase kinase kinase that can drive JNK activation, was found as an exocyst-associated protein in vivo. The exocyst is a Ral effector, and the epistasis between mutants of Ral and of msn, the fly ortholog of HGK, suggest the functional relevance of an exocyst/HGK interaction. Genetic analysis also showed that the exocyst is required for the execution of Ral function in apoptosis. We conclude that in Drosophila Ral counters apoptotic programs to support cell fate determination by acting as a negative regulator of JNK activity and a positive activator of p38 MAP kinase. We propose that the exocyst complex is Ral executioner in the JNK pathway and that a cascade from Ral to the exocyst to HGK would be a molecular basis of Ral action on JNK.

scholarly journals Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 376
Author(s):  
Chantal B. Lucini ◽  
Ralf J. Braun
Keyword(s):  
Cell Death ◽  
Oxygen Species ◽  
In Vivo Models ◽  
Dependent Cell ◽  
Cell Death Mechanisms ◽  
Sting Pathway ◽  
Mitochondrial Membrane Permeabilization

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

scholarly journals Programmed cell death 4 (PDCD4) expression during multistep Barrett's carcinogenesis

2010 ◽  
Vol 63 (8) ◽  
pp. 692-696 ◽  
Author(s):  
Matteo Fassan ◽  
Marco Pizzi ◽  
Giorgio Battaglia ◽  
Luciano Giacomelli ◽  
Paola Parente ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Intestinal Metaplasia ◽  
Negative Regulator ◽  
Pcr Analysis ◽  
Low Grade ◽  
Cytoplasmic Staining ◽  
Programmed Cell Death 4 ◽  
Columnar Metaplasia

AimTo test the contribution of programmed cell death 4 (PDCD4) tumour suppressor gene in Barrett's carcinogenesis.MethodsPDCD4 immunohistochemical expression was assessed in 88 biopsy samples obtained from histologically proven long-segment Barrett's mucosa (BM; 25 non-intestinal columnar metaplasia, 25 intestinal metaplasia (IM), 16 low-grade intraepithelial neoplasia (LG-IEN), 12 high-grade IEN (HG-IEN) and 10 Barrett's adenocarcinoma (BAc)). As controls, 25 additional samples of native oesophageal mucosa (N) were obtained from patients with dyspepsia. To further support the data, the expression levels of miR-21, an important PDCD4 expression regulator, in 14 N, 5 HG-IEN and 11 BAc samples were determined by quantitative real-time PCR analysis.ResultsPDCD4 immunostaining decreased progressively and significantly with the progression of the phenotypic changes occurring during Barrett's carcinogenesis (p<0.001). Normal basal squamous epithelial layers featured strong PDCD4 nuclear immunoreaction (mostly coexisting with weak–moderate cytoplasmic staining). Non-intestinal columnar metaplasia and intestinal metaplasia preserved a strong nuclear immunostaining; conversely, a significant decrease in PDCD4 nuclear expression was seen in dysplastic (LG-IEN and HG-IEN) and neoplastic lesions. Weak–moderate cytoplasmic immunostaining was evident in cases of LG-IEN, while HG-IEN and BAc samples showed weak cytoplasmic or no protein expression. As expected, miR-21 expression was significantly upregulated in HG-IEN and BAc samples, consistently with PDCD4 dysregulation.ConclusionsThese data support a significant role for PDCD4 downregulation in the progression of BM to BAc, and confirm miR-21 as a negative regulator of PDCD4 in vivo. Further efforts are needed to validate PDCD4 as a potential prognostic marker in patients with Barrett's oesophagus.

scholarly journals Apoptosis and in vivo models to study the molecules related to this phenomenon

2010 ◽  
Vol 8 (4) ◽  
pp. 495-497 ◽  
Author(s):  
Adriana Luchs ◽  
Claudia Pantaleão
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Ectopic Expression ◽  
B Cell Lymphoma ◽  
Murine Models ◽  
In Vivo Models ◽  
Large B Cell Lymphoma ◽  
Pathological Conditions ◽  
Pharmacological Targets

ABSTRACT Apoptosis or programmed cell death is a physiological process, essential for eliminating cells in excess or that are no longer necessary to the organism, acting on tissue homeostasis, although the phenomenon is also involved in pathological conditions. Apoptosis promotes activation of biochemical pathways inside cells called caspase pathway, of the proteins responsible for the cleavage of several cell substrates, leading to cell death. Antiapoptotic members of the Bcl-2 family (B cell CLL/lymphoma 2), that belong to the intrinsic route of the activation of caspases, such as Bcl-xL (extra-large B-cell lymphoma) and Bcl-w (Bcl-2-like 2), act predominantly to prevent that pro-apoptotic members, such as Bax (Bcl-2-associated X protein) and Bak (Bcl-2 relative bak) lead to cell death. Antiapoptotic molecules are considered potentially oncogenic. Murine models are known to be valuable systems for the experimental analysis of oncogenes in vivo, and for the identification of pharmacological targets for cancer and to assess antitumor therapies. Given the importance of tumorigenesis studies on the immune responses to cancer and the possibility of investigating the participation of antiapoptotic molecules in tumor progression in vivo, the development of new models may be platforms for studies on tumorigenesis, immune antitumor responses, investigation of the ectopic expression of antiapoptotic molecules and immunotherapies for tumors.

The N-terminal TPR region is the functional domain of SSN6, a nuclear phosphoprotein of Saccharomyces cerevisiae

1990 ◽  
Vol 10 (9) ◽  
pp. 4744-4756
Author(s):  
J Schultz ◽  
L Marshall-Carlson ◽  
M Carlson
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Function Analysis ◽  
Normal Growth ◽  
Negative Regulator ◽  
Tetratricopeptide Repeat ◽  
Functional Domain ◽  
Snf1 Kinase ◽  
C Terminus ◽  
Protein Functions

The SSN6 protein functions as a negative regulator of a variety of genes in Saccharomyces cerevisiae and is required for normal growth, mating, and sporulation. It is a member of a family defined by a repeated amino acid sequence, the TPR (tetratricopeptide repeat) motif. Here, we have used specific antibody to identify and characterize the SSN6 protein. Both SSN6 and a bifunctional SSN6-beta-galactosidase fusion protein were localized in the nucleus by immunofluorescence staining. The N-terminal one-third of the protein containing the TPR units was identified as the region that is important for SSN6 function. Analysis of four nonsense alleles, isolated as intragenic suppressors of an ssn6::URA3 insertion, revealed that polypeptides truncated after TPR unit 7 provide SSN6 function. Deletion analysis suggested that TPR units are required but that 4 of the 10 TPR units are sufficient. In addition, deletion studies indicated that three very long, homogeneous tracts of polyglutamine and poly(glutamine-alanine) are dispensable. Previous genetic evidence suggested the SSN6 protein as a possible target of the SNF1 protein kinase. Here, we show that the C terminus of SSN6 is phosphorylated in vivo and that the SNF1 kinase is not responsible for most of the phosphorylation. Finally, SSN6 has a modest effect on the maintenance of minichromosomes.

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.

Sign in / Sign up

Export Citation Format

Share Document