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Estudo funcional da prote??na quinase JNK de Schistosoma mansoniatrav??s de express??o heter??loga no organismo modelo Caenorhabditis elegans

Gava, Sandra Grossi
Fonte: s.n. Publicador: s.n.
Tipo: Dissertação
PT_BR
Relevância na Pesquisa
27.12%
A identifica????o e caracteriza????o dos mecanismos e mol??culas envolvidos em sinaliza????o celular s??o essenciais para o entendimento da biologia parasit??ria do S. mansoni. Prote??na quinases desempenham papel chave em vias de sinaliza????o e tem sido propostas como potenciais alvos para o desenvolvimento de novas drogas anti-Schistosoma. Visto que a caracteriza????o funcional em S. mansoni ?? dificultada por limita????es nos m??todos de transforma????o gen??tica deste parasito, o presente estudo prop??e o uso de C. elegans como um modelo para a express??o heter??loga de genes de S. mansonique codificam prote??nas quinases. Genes que codificam prote??na quinases em S. mansoni, hom??logos aos identificados em C. elegans, foram selecionados pelo nosso grupo a partir do proteoma do parasito atrav??s de uma abordagem filogen??mica. Inicialmente, foi selecionada a prote??na quinase JNK, que participa da via de sinaliza????o das MAP quinases para a realiza????o das an??lises experimentais. Em C. elegans, a prote??na JNK est?? relacionada ao aumento de longevidade e da resist??ncia aos estresses t??rmico e oxidativo. Oligonucleot??deos espec??ficos foram desenhados para amplificar a regi??o promotora do gene em C. elegans bem como as regi??es codificantes (CDS) em ambos os organismos. A regi??o promotora foi amplificada a partir do DNA gen??mico extra??do de C. elegans adultos. O RNA total foi extra??do de esquistoss??mulos e C. elegans adultos. As CDS foram amplificadas a partir do cDNA sintetizado e os fragmentos de DNA resultantes foram clonados em E. coliDH5??. As constru????es obtidas foram digeridas com enzimas de restri????o selecionadas de forma a linearizar o vetor contendo a regi??o promotora e recuperar as CDS. Posteriormente...

Silencing of WNK2 is associated with upregulation of MMP2 and JNK in gliomas

Costa, Angela Margarida; Pinto, Filipe; Martinho, Olga; Oliveira, Maria José; Jordan, Peter; Reis, Rui Manuel
Fonte: Impactjournal Publicador: Impactjournal
Tipo: Artigo de Revista Científica
Publicado em //2014 ENG
Relevância na Pesquisa
36.78%
Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade extracellular matrix (ECM), thus assisting invasion. Upregulation of MMPs, frequently reported in gliomas, is associated with aggressive behavior. WNK2 is a tumor suppressor gene expressed in normal brain, and silenced by promoter methylation in gliomas. Patients without WNK2 exhibited poor prognosis, and its downregulation was associated with increased glioma cell invasion. Here we showed that MMP2 expression and activity are increased in glioma cell lines that do not express WNK2. Also, WNK2 inhibited JNK, a process associated with decreasing levels of MMP2. Thus, WNK2 promoter methylation and silencing in gliomas is associated with increased JNK activation and MMP2 expression and activity, thus explaining in part tumor cell invasion potential.

Co-localization of GSTP1 and JNK in transitional cell carcinoma of urinary bladder

Pljesa-Ercegovac,Marija; Savic-Radojevic,Ana; Kravic-Stevovic,Tamara; Bumbasirevic,Vladimir; Mimic-Oka,Jasmina; Simic,Tatiana
Fonte: Sociedade Brasileira de Genética Publicador: Sociedade Brasileira de Genética
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2010 EN
Relevância na Pesquisa
37.07%
Transitional cell carcinoma (TCC) of urinary bladder belongs to glutathione S-transferase P1 (GSTP1) overexpressing tumors. Upregulated GSTP1 in TCC is related to apoptosis inhibition. This antiapoptotic effects of GSTP1 might be mediated through protein:protein interaction with c-Jun NH2-terminal kinase (JNK). Herein, we analyzed whether a direct link between GSTP1 and JNK exists in TCC. The presence of GSTP1/JNK complexes was analyzed by immunoprecipitation and Western blotting in 20 TCC specimens, obtained after surgery. Co-localization of GSTP1 and JNK was also investigated in the 5637 TCC cell line by immunofluorescence confocal microscopy. By means of immunoprecipitation we show for the first time the presence of GSTP1/JNK complexes in all TCC samples studied. A co-localization of GSTP1 and JNK was also demonstrated in the 5637 TCC cell line by means of confocal microscopy. Protein-protein interactions, together with co-localization between GSTP1 and JNK provide evidence that GSTP1 most probably inhibits apoptosis in TCC cells by non-covalent binding to JNK.

Preferential activation of the p46 isoform of JNK/SAPK in mouse macrophages by TNFα

Chan, Edward D.; Winston, Brent W.; Jarpe, Matthew B.; Wynes, Murry W.; Riches, David W. H.
Fonte: The National Academy of Sciences of the USA Publicador: The National Academy of Sciences of the USA
Tipo: Artigo de Revista Científica
Publicado em 25/11/1997 EN
Relevância na Pesquisa
27.12%
A pleiotropic cytokine, tumor necrosis factor-α (TNFα), regulates the expression of multiple macrophage gene products and thus contributes a key role in host defense. In this study, we have investigated the specificity and mechanism of activation of members of the c-Jun-NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) subfamily of mitogen-activated protein kinases (MAPKs) in mouse macrophages in response to stimulation with TNFα. Exposure of macrophages to TNFα stimulated a preferential increase in catalytic activity of the p46 JNK/SAPK isoform compared with the p54 JNK/SAPK isoform as determined by: (i) separation of p46 and p54 JNK/SAPKs by anion exchange liquid chromatography and (ii) selective immunodepletion of the p46 JNK/SAPK from macrophage lysates. To investigate the level of regulation of p46 JNK/SAPK activation, we determined the ability of MKK4/SEK1/JNKK, an upstream regulator of JNK/SAPKs, to phosphorylate recombinant kinase-inactive p46 and p54 JNK/SAPKs. Endogenous MKK4 was able to transphosphorylate both isoforms. In addition, both the p46 and p54 JNK/SAPK isoforms were phosphorylated on their TPY motif in response to TNFα stimulation as reflected by immunoblotting with a phospho-specific antibody that recognizes both kinases. Collectively...

jkk-1 and mek-1 regulate body movement coordination and response to heavy metals through jnk-1 in Caenorhabditis elegans

Villanueva, Alberto; Lozano, José; Morales, Albert; Lin, Xinhua; Deng, Xinzhu; Hengartner, Michael O.; Kolesnick, Richard N.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Publicado em 17/09/2001 EN
Relevância na Pesquisa
27.16%
Although in vitro evidence suggests two c-Jun N-terminal kinase (JNK) kinases, MKK4 and MKK7, transactivate JNK, in vivo confirmation is incomplete. In fact, JNK deficiency may differ from the composite deficiency of MKK4 and MKK7 in Drosophila and mice. Recently, the Caenorhabditis elegans homolog of human JNK, jnk-1, and two MKK-7s, mek-1 and jkk-1, were cloned. Here we characterize jnk-1, which encodes two isoforms JNK-1α and JNK-1β. A null allele, jnk-1(gk7), yielded worms with defective body movement coordination and modest mechanosensory deficits. Similarly to jkk-1 mutants, elimination of GABAergic signals suppressed the jnk-1(gk7) locomotion defect. Like mek-1 nulls, jnk-1(gk7) showed copper and cadmium hypersensitivity. Conditional expression of JNK-1 isoforms rescued these defects, suggesting that they are not due to developmental errors. While jkk-1 or mek-1 inactivation mimicked jnk-1(gk7) locomotion and heavy metal stress defects, respectively, mkk-4 inactivation did not, but rather yielded defective egg laying. Our results delineate at least two different JNK pathways through jkk-1 and mek-1 in C.elegans, and define interaction between MKK7, but not MKK4, and JNK.

Glucocorticoid receptor–JNK interaction mediates inhibition of the JNK pathway by glucocorticoids

Bruna, Alejandra; Nicolàs, Marta; Muñoz, Alberto; Kyriakis, John M.; Caelles, Carme
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Publicado em 17/11/2003 EN
Relevância na Pesquisa
27.13%
Inhibition of the c-Jun N-terminal kinase (JNK) pathway by glucocorticoids (GCs) results in AP-1 repression. GC antagonism of AP-1 relies mainly on the transrepression function of the GC receptor (GR) and mediates essential physiological and pharmacological actions. Here we show that GCs induce the disassembly of JNK from mitogen-activated protein kinase kinase 7 (MKK7) by promoting its association with GR. Moreover, we have characterized a hormone-regulated JNK docking site in the GR ligand-binding domain that mediates GR–JNK interaction. The binding of GR to JNK is required for inhibition of JNK activation and induction of inactive JNK nuclear transfer by GCs. The dissociation of these two hormone actions shows that JNK nuclear transfer is dispensable for the downregulation of JNK activation by GCs. Nonetheless, nuclear accumulation of inactive JNK may still be relevant for enhancing the repression of AP-1 activity by GCs. In this regard, chromatin immunoprecipitation assays show that GC-induced GR–JNK association correlates with an increase in the loading of inactive JNK on the AP-1-bound response elements of the c-jun gene.

Regulation of JNK signaling by GSTp.

Adler, V; Yin, Z; Fuchs, S Y; Benezra, M; Rosario, L; Tew, K D; Pincus, M R; Sardana, M; Henderson, C J; Wolf, C R; Davis, R J; Ronai, Z
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/03/1999 EN
Relevância na Pesquisa
27.16%
Studies of low basal Jun N-terminal kinase (JNK) activity in non-stressed cells led us to identify a JNK inhibitor that was purified and identified as glutathione S-transferase Pi (GSTp) and was characterized as a JNK-associated protein. UV irradiation or H2O2 treatment caused GSTp oligomerization and dissociation of the GSTp-JNK complex, indicating that it is the monomeric form of GSTp that elicits JNK inhibition. Addition of purified GSTp to the Jun-JNK complex caused a dose-dependent inhibition of JNK activity. Conversely, immunodepleting GSTp from protein extracts attenuated JNK inhibition. Furthermore, JNK activity was increased in the presence of specific GSTp inhibitors and a GSTp-derived peptide. Forced expression of GSTp decreased MKK4 and JNK phosphorylation which coincided with decreased JNK activity, increased c-Jun ubiquitination and decreased c-Jun-mediated transcription. Co-transfection of MEKK1 and GSTp restored MKK4 phosphorylation but did not affect GSTp inhibition of JNK activity, suggesting that the effect of GSTp on JNK is independent of the MEKK1-MKK4 module. Mouse embryo fibroblasts from GSTp-null mice exhibited a high basal level of JNK activity that could be reduced by forced expression of GSTp cDNA. In demonstrating the relationships between GSTp expression and its association with JNK...

Role of JNK Translocation to Mitochondria Leading to Inhibition of Mitochondria Bioenergetics in Acetaminophen-induced Liver Injury*S⃞

Hanawa, Naoko; Shinohara, Mie; Saberi, Behnam; Gaarde, William A.; Han, Derick; Kaplowitz, Neil
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 16/05/2008 EN
Relevância na Pesquisa
27.19%
Previously, we demonstrated JNK plays a central role in acetaminophen (APAP)-induced liver injury (Gunawan, B. K., Liu, Z. X., Han, D., Hanawa, N., Gaarde, W. A., and Kaplowitz, N. (2006) Gastroenterology 131, 165–178). In this study, we examine the mechanism involved in activating JNK and explore the downstream targets of JNK important in promoting APAP-induced liver injury in vivo. JNK inhibitor (SP600125) was observed to significantly protect against APAP-induced liver injury. Increased mitochondria-derived reactive oxygen species were implicated in APAP-induced JNK activation based on the following: 1) mitochondrial GSH depletion (maximal at 2 h) caused increased H2O2 release from mitochondria, which preceded JNK activation (maximal at 4 h); 2) treatment of isolated hepatocytes with H2O2 or inhibitors (e.g. antimycin) that cause increased H2O2 release from mitochondria-activated JNK. An important downstream target of JNK following activation was mitochondria based on the following: 1) JNK translocated to mitochondria following activation; 2) JNK inhibitor treatment partially protected against a decline in mitochondria respiration caused by APAP treatment; and 3) addition of purified active JNK to mitochondria isolated from mice treated with APAP plus JNK inhibitor (mitochondria with severe GSH depletion...

JNK regulates serotonin-mediated proliferation and migration of pulmonary artery smooth muscle cells

Wei, Lin; Liu, Yinglin; Kaneto, Hideaki; Fanburg, Barry L.
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.16%
JNK is a member of the MAPK family and has essential roles in inflammation and cell differentiation and apoptosis. In recent years, there have been accumulating data indicating a novel role for JNK in cell growth and migration. In this report, we demonstrate that JNK activity is necessary for serotonin (5-HT)-induced proliferation and migration of bovine pulmonary artery smooth muscle cells (PASMCs). Stimulation with 5-HT was found to lead to activation of JNK with a maximal activation at 10 min. Inhibition of JNK with its specific inhibitor, SP-600125, or its dominant-negative form, DN-JNK, significantly reduced 5-HT-stimulated [3H]thymidine incorporation and cyclin D1 expression. A similar inhibitory effect on SMC migration produced by 5-HT, as detected by a wound healing assay, was observed with inhibition of JNK. Furthermore, inhibition of 5-HT receptors 1B and 2A, but not inhibition of the 5-HT transporter, blocked 5-HT-induced JNK activation. Inhibition of phosphatidylinositol 3-kinase (PI3K) with LY-294002 and wortmannin had little or no effect on 5-HT-induced JNK phosphorylation, but JNK inhibitor SP-600125 and DN-JNK blocked 5-HT-stimulated phosphorylation of Akt and its downstream effectors, p70S6K1 and S6, indicating that Akt is a downstream effector of JNK. Activation of Akt by 5-HT was blocked only minimally...

Mitochondrial c-Jun N-terminal Kinase (JNK) Signaling Initiates Physiological Changes Resulting in Amplification of Reactive Oxygen Species Generation*

Chambers, Jeremy W.; LoGrasso, Philip V.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.16%
The JNK signaling cascade is critical for cellular responses to a variety of environmental and cellular stimuli. Although gene expression aspects of JNK signal transduction are well studied, there are minimal data on the physiological impact of JNK signaling. To bridge this gap, we investigated how JNK impacted physiology in HeLa cells. We observed that inhibition of JNK activity and JNK silencing with siRNA reduced the level of reactive oxygen species (ROS) generated during anisomycin-induced stress in HeLa cells. Silencing p38 had no significant impact on ROS generation under anisomycin stress. Moreover, JNK signaling mediated amplification of ROS production during stress. Mitochondrial superoxide production was shown to be the source of JNK-induced ROS amplification, as an NADPH oxidase inhibitor demonstrated little impact on JNK-mediated ROS generation. Using mitochondrial isolation from JNK null fibroblasts and targeting the mitochondrial scaffold of JNK, Sab, we demonstrated that mitochondrial JNK signaling was responsible for mitochondrial superoxide amplification. These results suggest that cellular stress altered mitochondria, causing JNK to translocate to the mitochondria and amplify up to 80% of the ROS generated largely by Complex I. This work demonstrates that a sequence of events exist for JNK mitochondrial signaling whereby ROS activates JNK...

Joint inhibition of TOR and JNK pathways interacts to extend the lifespan of Brachionus manjavacas (Rotifera)

Snell, Terry W.; Johnston, Rachel K.; Rabeneck, Brett; Zipperer, Cody; Teat, Stephanie
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.13%
The TOR kinase pathway is central in modulating aging in a variety of animal models. The target of rapamycin (TOR) integrates a complex network of signals from growth conditions, nutrient availability, energy status, and physiological stresses and matches an organism’s growth rate to the resource environment. Important problems remaining are to identify the pathways that interact with TOR and characterize them as additive or synergistic. One of the most versatile stress sensors in metazoans is the Jun-N-terminal Kinase (JNK) signalling pathway. JNK is an evolutionarily conserved stress-activated protein kinase that is induced by a range of stressors, including UV irradiation, reactive oxygen species, DNA damage, heat, and bacterial antigens. JNK is thought to interact with the TOR pathway, but its effects on TOR are poorly understood. We used the rotifer Brachionus manjavacas as a model animal to probe the regulation of TOR and JNK pathways and explore their interaction. The effect of various chemical inhibitors was examined in life table and stressor challenge experiments. A survey of 12 inhibitors revealed two, rapamycin and JNK inhibitor, that significantly extended lifespan of B. manjavacas. At 1 μM concentration, exposure to rapamycin or JNK inhibitor extended mean rotifer lifespan by 35% and maximum lifespan by 37%. Exposure to both rapamycin and JNK inhibitor simultaneously extended mean rotifer lifespan 65% more than either alone. Exposure to a combination of rapamycin and JNK inhibitors conveyed greater protection to starvation...

The Notch-mediated hyperplasia circuitry in Drosophila reveals a Src-JNK signaling axis

Ho, Diana M; Pallavi, SK; Artavanis-Tsakonas, Spyros
Fonte: eLife Sciences Publications, Ltd Publicador: eLife Sciences Publications, Ltd
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
36.87%
Notch signaling controls a wide range of cell fate decisions during development and disease via synergistic interactions with other signaling pathways. Here, through a genome-wide genetic screen in Drosophila, we uncover a highly complex Notch-dependent genetic circuitry that profoundly affects proliferation and consequently hyperplasia. We report a novel synergistic relationship between Notch and either of the non-receptor tyrosine kinases Src42A and Src64B to promote hyperplasia and tissue disorganization, which results in cell cycle perturbation, JAK/STAT signal activation, and differential regulation of Notch targets. Significantly, the JNK pathway is responsible for the majority of the phenotypes and transcriptional changes downstream of Notch-Src synergy. We previously reported that Notch-Mef2 also activates JNK, indicating that there are commonalities within the Notch-dependent proliferation circuitry; however, the current data indicate that Notch-Src accesses JNK in a significantly different fashion than Notch-Mef2. DOI: http://dx.doi.org/10.7554/eLife.05996.001

Maintenance of tissue homeostasis by receptor tyrosine kinase (RTK) and Jun-N-terminal kinase (JNK)

Luo, Xi ; Jasper, Heinrich
Fonte: Universidade de Rochester Publicador: Universidade de Rochester
Tipo: Tese de Doutorado Formato: Number of Pages:x, 117 leaves
ENG
Relevância na Pesquisa
36.65%
Thesis (Ph. D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Biomedical Genetics, 2008.; Maintenance of homeostasis is crucial for the development and survival of the multi-cellular organisms. Intrinsically, proper mitogenic and differentiation signals have to be accurately delivered for the cell to adopt the right cell fate. Extrinsically, as organisms are constantly challenged by environmental insults, damaged cells have to be either salvaged or sacrificed to keep the integrity of the whole organism. Thus, mechanisms that govern cell specification and/or correct/eliminate malfunctioned cells are expected to serve as safeguard for the body since such cells pose a threat to the organism by exhibiting uncontrolled proliferation, growth or cell death. Misregulation of these cellular behaviors is linked to the onset and progression of human diseases, notably cancer and neurodegenerative diseases. In the first part of our study, we have carried out experiments to demonstrate that JNK mediates an apoptotic response to remove UV-damaged tissues by upregulating the proapoptotic gene hid. This transcription-dependent apoptotic response relies on the cooperation of two downstream transcription factors, Fos and FoxO...

JNK-Regulated Autophagy as a Defensive Mechanism Against Oxidative Stress in Drosophila Melanogaster

Wu, Hai ; Bohmann, Dirk
Fonte: Universidade de Rochester Publicador: Universidade de Rochester
Tipo: Tese de Doutorado
ENG
Relevância na Pesquisa
37.16%
Thesis (Ph.D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Biomedical Genetics, 2009.; Organisms commonly encounter oxidative stress originating from endogenous sources or in the form of exogenous stressors. Oxidative stress has been implicated in the pathogenesis of various diseases and aging. Thus, boosting the resistance against oxidative stress might be a strategy to delay or prevent the onset of diseases, promote organismal survival, and slow down aging. Recent findings have implicated autophagy, a conserved catabolic process, into the cellular defense against various biological and xenobiotic stresses including oxidative stress. However, the regulation of autophagy in response to oxidative stress remains largely elusive. One central regulatory system of the organism’s defense against oxidative stress is the JNK pathway. It has been shown previously that JNK gain-of-function mutants are more resistant to acute stress exposure. Furthermore, the JNK pathway has been reported to affect the lifespan of metazoans, presumably be deflecting oxidative damage. The downstream effectors of JNK in this context are not completely understood. In this thesis, I studied the regulation of autophagy by JNK signaling upon oxidative stress exposure...

JNK signaling is needed to tolerate chromosomal instability

Wong, H.; Shaukat, Z.; Wang, J.; Saint, R.; Gregory, S.
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
Publicado em //2014 EN
Relevância na Pesquisa
37.01%
Chromosomal instability (CIN), as a common feature of tumors, represents a potential therapeutic target if ways can be found to specifically cause apoptosis in unstably dividing cells. We have previously shown that if signaling through the JNK pathway is reduced, apoptosis is triggered in models of chromosomal instability induced by loss of the spindle checkpoint. Here we identify components upstream and downstream of JNK that are able to mediate this effect, and test the involvement of p53 and DNA damage in causing apoptosis when JNK signaling is reduced in CIN cells. We show that cell cycle progression timing has a strong effect on the apoptosis seen when JNK signaling is reduced in genetically unstable cells: a shortened G₂ phase enhances the apoptosis, while lengthening G₂ rescues the JNK-deficient CIN cell death phenotype. Our findings suggest that chromosomal instability represents a significant stress to dividing cells, and that without JNK signaling, cells undergo apoptosis because they lack a timely and effective response to DNA damage.; Heidi W-S Wong, Zeeshan Shaukat, Jianbin Wang, Robert Saint, and Stephen L Gregory; Published Online 12 Dec 2013

The natural triterpene maslinic acid induces apoptosis in HT29 colon cancer cells by a JNK-p53-dependent mechanism

Reyes Zurita, Fernando Jes??s; Pach??n Pe??a, Gisela; Liz??rraga, Daneida; Rufino Palomares, Eva Encarnaci??n; Cascante Serratosa, Marta; Lupi????ez Cara, Jos?? Antonio
Fonte: Biomed Central Publicador: Biomed Central
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
36.78%
[Background] Maslinic acid, a pentacyclic triterpene found in the protective wax-like coating of the leaves and fruit of Olea europaea L., is a promising agent for the prevention of colon cancer. We have shown elsewhere that maslinic acid inhibits cell proliferation to a significant extent and activates mitochondrial apoptosis in colon cancer cells. In our latest work we have investigated further this compound's apoptotic molecular mechanism. [Methods] We used HT29 adenocarcinoma cells. Changes genotoxicity were analyzed by single-cell gel electrophoresis (comet assay). The cell cycle was determined by flow cytometry. Finally, changes in protein expression were examined by western blotting. Student's t-test was used for statistical comparison. [Results] HT29 cells treated with maslinic acid showed significant increases in genotoxicity and cell-cycle arrest during the G0/G1 phase after 72 hours' treatment and an apoptotic sub-G0/G1 peak after 96 hours. Nevertheless, the molecular mechanism for this cytotoxic effect of maslinic acid has never been properly explored. We show here that the anti-tumoral activity of maslinic acid might proceed via p53-mediated apoptosis by acting upon the main signaling components that lead to an increase in p53 activity and the induction of the rest of the factors that participate in the apoptotic pathway. We found that in HT29 cells maslinic acid activated the expression of c-Jun NH2-terminal kinase (JNK)...

Ursolic acid induces cell death and modulates autophagy through JNK pathway in apoptosis-resistant colorectal cancer cells

Xavier, Cristina P. R.; Lima, Cristóvão F.; Pedro, Dalila Fernanda Neto; Wilson, Jonathan M.; Kristiansen, K.; Wilson, Cristina Pereira
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em //2013 ENG
Relevância na Pesquisa
36.93%
Colorectal carcinomas (CRCs) with P53 mutations have been shown to be resistant to chemotherapy with 5-fluorouracil (5-FU), the most widely used chemotherapeutic drug for CRC treatment. Autophagy is emerging as a promising therapeutic target for drug-resistant tumors. In the present study, we tested the effects of ursolic acid (UA), a natural triterpenoid, on cell death mechanisms and its effects in combination with 5-FU in the HCT15 p53 mutant apoptosis-resistant CRC cell line. The involvement of UA in autophagy and its in vivo efficacy were evaluated. Our data show that UA induces apoptosis independent of caspases in HCT15 cells and enhances 5-FU effects associated with an activation of c-jun N-terminal kinase (JNK). In this cell line, where this compound has a more pronounced effect on the induction of cell death compared to 5-FU, apoptosis corresponds only to a small percentage of the total cell death induced by UA. UA also modulated autophagy by inducing the accumulation of LC3 and p62 levels with involvement of JNK pathway, which indicates a contribution of autophagy on JNK-dependent induction of cell death by UA. By using nude mice xenografted with HCT15 cells, we verified that UA was also active in vivo decreasing tumor growth rate. In conclusion...

Natural triterpenic diols promote apoptosis in astrocytoma cells through ROS-mediated mitochondrial depolarization and JNK activation

Martín, Rubén; Ibeas, Elvira; Carvalho-Tavares, Juliana; Hernández, Marita; Ruiz-Gutiérrez, Valentina; Nieto, María Luisa
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artículo Formato: 877431 bytes; application/pdf
ENG
Relevância na Pesquisa
36.78%
[Background]: Triterpene alcohols and acids are multifunctional compounds widely distributed throughout the plant kingdom that exhibit a variety of beneficial health properties, being synthetic analogs of oleanolic acid under clinical evaluation as anti-tumoral therapeutic agents. However, the antineoplastic activity of two natural occuring triterpenoid alcohols extracted from olive oil, erythrodiol (an intermediate from oleanolic acid), and its isomer, uvaol, has barely been reported, particularly on brain cancer cells. Astrocytomas are among the most common and aggressive type of primary malignant tumors in the neurological system lacking effective treatments, and in this study, we addressed the effect of these two triterpenic diols on the human 1321N1 astrocytoma cell line.; [Principal Findings]: Erythrodiol and uvaol effectively affected cell proliferation, as well as cell cycle phases and induced 1321N1 cell death. Both triterpenes successfully modulated the apoptotic response, promoting nuclear condensation and fragmentation. They caused retraction and rounding of cultured cells, which lost adherence from their supports, while F-actin and vimentin filaments disappeared as an organized cytoplasmic network. At molecular level, changes in the expression of surface proteins associated with adhesion or death processes were also observed. Moreover...

Transient activation of the c-Jun N-terminal kinase (JNK) activity by ligation of the tetraspan CD53 antigen in different cell types

Yunta, M.; Oliva, José Luis; Barcia, R.; Lazo, Pedro A.
Fonte: Wiley-Blackwell Publicador: Wiley-Blackwell
Tipo: Artículo Formato: 346197 bytes; application/pdf
ENG
Relevância na Pesquisa
36.93%
TheCD53 antigen is amember of the tetraspaninmembrane protein family that is expressed in the lymphoid-myeloid lineage.We have studied the implication of CD53 antigen in signal transduction by determining the effect of its ligation on the c-Jun N-terminal kinase (JNK) in different cell types. Ligation of the rat or human CD53 antigen induces a three- to fourfold transient activation of JNKactivity that peaks at 3±5 min.The effect was detected by assaying the endogenous or exogenous (transfected) JNKactivity. The JNK response was detected in IR938F cells, a rat B-cell lymphoma, and in Jurkat cells derived from a human T-cell lymphoma. This JNK activation was not mediated by the vav oncogene, and CD53 does not cooperate with CD3 for vav activation. Asimilar JNKactivation was also detected in a human renal carcinoma cell line that was transiently transfected with the human CD53 cDNA to mimic the CD53 ectopic expression in carcinomas. In stable CD53-transfected cells it stimulated Jun-dependent transcriptional activity. We conclude that parts of the cell responses modulated by the CD53 are mediated by JNK activation, and this activation is independent of the different protein interactions that the CD53 protein has on speci®c cell types.; This work was supported by grants from Ministerio de Ciencia y TecnologõÂa (SAF2000/0169)...

Role of JNK isoforms in the development of neuropathic pain following sciatic nerve transection in the mouse

Manassero, Giusi; Repetto, Ivan E.; Cobianchi, Stefano; Valsecchi, Valeria; Bonny, Christophe; Rossi, Ferdinando; Vercelli, Alessandro
Fonte: Universidade Autônoma de Barcelona Publicador: Universidade Autônoma de Barcelona
Tipo: Artigo de Revista Científica Formato: application/pdf; image/jpeg; image/jpeg
Publicado em //2012 ENG
Relevância na Pesquisa
37.12%
Background: Current tools for analgesia are often only partially successful, thus investigations of new targets for pain therapy stimulate great interest. Consequent to peripheral nerve injury, c-Jun N-terminal kinase (JNK) activity in cells of the dorsal root ganglia (DRGs) and spinal cord is involved in triggering neuropathic pain. However, the relative contribution of distinct JNK isoforms is unclear. Using knockout mice for single isoforms, and blockade of JNK activity by a peptide inhibitor, we have used behavioral tests to analyze the contribution of JNK in the development of neuropathic pain after unilateral sciatic nerve transection. In addition, immunohistochemical labelling for the growth associated protein (GAP)-43 and Calcitonin Gene Related Peptide (CGRP) in DRGs was used to relate injury related compensatory growth to altered sensory function. Results: Peripheral nerve injury produced pain–related behavior on the ipsilateral hindpaw, accompanied by an increase in the percentage of GAP43-immunoreactive (IR) neurons and a decrease in the percentage of CGRP-IR neurons in the lumbar DRGs. The JNK inhibitor, D-JNKI-1, successfully modulated the effects of the sciatic nerve transection. The onset of neuropathic pain was not prevented by the deletion of a single JNK isoform...