scholarly journals Gab1 Is an Integrator of Cell Death versus Cell Survival Signals in Oxidative Stress

2003 ◽  
Vol 23 (13) ◽  
pp. 4471-4484 ◽  
Author(s):  
Marina Holgado-Madruga ◽  
Albert J. Wong
Keyword(s):  
Oxidative Stress ◽  
Growth Factors ◽  
Cell Survival ◽  
Signaling Pathways ◽  
Kinase Inhibitor ◽  
Large Body ◽  
Wild Type Mouse ◽  
Homozygous Deletion ◽  
Dependent Manner ◽  
Jnk Activation

ABSTRACT Upon the addition of different growth factors and cytokines, the Gab1 docking protein is tyrosine phosphorylated and in turn activates different signaling pathways. On the basis of the large body of evidence concerning cross talk between the signaling pathways activated by growth factors and oxidative stress, we decided to investigate the role of Gab1 in oxidative injury. We stimulated wild-type mouse embryo fibroblasts (MEF) or MEF with a homozygous deletion of the Gab1 gene (−/− MEF) with H2O2. Our results show that Gab1 is phosphorylated in a dose- and time-dependent manner after H2O2 triggering. Gab1 then recruits molecules such as SHP2, phosphatidylinositol 3-kinase (PI3K), and Shc. Gab1 phosphorylation is sensitive to the Src family kinase inhibitor PP2. Furthermore, we demonstrate that Gab1 is required for H2O2-induced c-Jun N-terminal kinase (JNK) activation but not for ERK2 or p38 activation. Reconstitution of Gab1 in −/− MEF rescues JNK activation, and we find that this is dependent on the SHP2 binding site in Gab1. Cell viability assays reveal that Gab1 has a dual role in cell survival: a positive one through its interaction with PI3K and a negative one through its interaction with SHP2. This is the first report identifying Gab1 as a component in oxidative stress signaling and one that is required for JNK activation.

scholarly journals Anethole induces anti-oral cancer activity by triggering apoptosis, autophagy and oxidative stress and by modulation of multiple signaling pathways

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Camille Contant ◽  
Mahmoud Rouabhia ◽  
Lionel Loubaki ◽  
Fatiha Chandad ◽  
Abdelhabib Semlali
Keyword(s):  
Oxidative Stress ◽  
Cell Proliferation ◽  
Oral Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Kinase Inhibitor ◽  
Epithelial Mesenchymal Transition ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
And Oxidative Stress

AbstractOral cancer is one of the major public health problems. The aim of this study was to evaluate the effects of anethole, 1-methoxy-4-[(E)-1-propenyl]-benzene, on growth and apoptosis of oral tumor cells, and to identify the signaling pathways involved in its interaction with these cancer cells. Cancer gingival cells (Ca9-22) were treated with different concentrations of anethole. Cell proliferation and cytotoxic effects were measured by MTT and LDH assays. Cell death, autophagy and oxidative stress markers were assessed by flow cytometry while cell migration was determined by a healing capacity assay. The effect of anethole on apoptotic and pro-carcinogenic signaling pathways proteins was assessed by immunoblotting. Our results showed that anethole selectively and in a dose-dependent manner decreases the cell proliferation rate, and conversely induces toxicity and apoptosis in oral cancer cells. This killing effect was mediated mainly through NF-κB, MAPKinases, Wnt, caspase 3, 9 and PARP1 pathways. Anethole showed an ability to induce autophagy, decrease reactive oxygen species (ROS) production and increased intracellular glutathione (GSH) activity. Finally, anethole treatment inhibits the expression of oncogenes (cyclin D1) and up-regulated cyclin-dependent kinase inhibitor (p21WAF1), increases the expression of p53 gene, but inhibits the epithelial-mesenchymal transition markers. These results indicate that anethole could be a potential molecule for the therapy of oral cancer.

scholarly journals IGFs stimulate zebrafish cell proliferation by activating MAP kinase and PI3-kinase-signaling pathways

2001 ◽  
Vol 280 (4) ◽  
pp. R1230-R1239 ◽  
Author(s):  
Kasiani C. Pozios ◽  
Jun Ding ◽  
Brian Degger ◽  
Zee Upton ◽  
Cunming Duan
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase ◽  
Dna Synthesis ◽  
Signaling Pathways ◽  
Kinase Inhibitor ◽  
Pi3 Kinase ◽  
Dependent Manner ◽  
Embryonic Cells ◽  
Kinase Signaling ◽  
Igf I

Insulin-like growth factor (IGF)-I and -II have been cloned from a number of teleost species, but their cellular actions in fish are poorly defined. In this study, we show that both IGF-I and -II stimulated zebrafish embryonic cell proliferation and DNA synthesis in a concentration-dependent manner, whereas insulin had little mitogenic activity. Affinity cross-linking and immunoblotting studies revealed the presence of IGF receptors with the characteristics of the mammalian type I IGF receptor. Competitive binding assay results indicated that the binding affinities of the zebrafish IGF-I receptors to IGF-I, IGF-II, and insulin are 1.9, 2.6, and >190 nM, indicating that IGF-I and -II bind to the IGF-I receptor(s) with approximately equal high affinity. To further investigate the cellular mechanism of IGF actions, we have studied the effects of IGFs on two major signal transduction pathways: mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3 kinase). IGFs activated MAPK in zebrafish embryonic cells in a dose-dependent manner. This activation occurred within 5 min of IGF-I stimulation and disappeared after 1 h. IGF-I also caused a concentration-dependent activation of protein kinase B, a downstream target of PI3 kinase, this activation being sustained for several hours. Inhibition of MAPK activation by the MAPK kinase inhibitor PD-98059 inhibited the IGF-I-stimulated DNA synthesis. Similarly, use of the PI3 kinase inhibitor LY-294002 also inhibited IGF-I-stimulated DNA synthesis. When both the MAPK and PI3 kinase pathways were inhibited using a combination of these compounds, the IGF-I-stimulated DNA synthesis was completely negated. These results indicate that both IGF-I and -II are potent mitogens for zebrafish embryonic cells and that activation of both the MAPK and PI3 kinase-signaling pathways is required for the mitogenic action of IGFs in zebrafish embryonic cells.

scholarly journals SchisandraLignan Extract Protects against Carbon Tetrachloride-Induced Liver Injury in Mice by Inhibiting Oxidative Stress and Regulating the NF-κB and JNK Signaling Pathways

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Qingshan Chen ◽  
Qi Zhan ◽  
Ying Li ◽  
Sen Sun ◽  
Liang Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Signaling Pathways ◽  
Active Components ◽  
Traditional Chinese Herbal Medicine ◽  
Action Mechanisms ◽  
Antioxidative Stress ◽  
Jnk Activation ◽  
Different Doses

Schisandra chinensis(S. chinensis) is a traditional Chinese herbal medicine widely used for the treatment of liver disease, whose main active components are lignans. However, the action mechanisms of the lignans inS. chinensisremain unclear. This study aimed to investigate the protective effect and related molecular mechanism ofSchisandralignan extract (SLE) against carbon tetrachloride- (CCl4-) induced acute liver injury in mice. Different doses of SLE at 50, 100, and 200 mg/kg were administered daily by gavage for 5 days before CCl4treatment. The results showed that SLE significantly decreased the activities of serum ALT/AST and reduced liver pathologic changes induced by CCl4. Pretreatment with SLE not only decreased the content of MDA but increased SOD, GSH, and GSH-Px activities in the liver, suggesting that SLE attenuated CCl4-induced oxidative stress. The expression levels of inflammatory cytokines TNF-a, IL-1β, and IL-6 were decreased after oral administration of SLE, probably because lignans inhibited the NF-κB activity. Additionally, SLE also inhibited hepatocyte apoptosis by suppressing JNK activation and regulating Bcl-2/Bax signaling pathways. In conclusion, these results suggested that SLE prevented CCl4-induced liver injury through a combination of antioxidative stress, anti-inflammation, and antihepatocyte apoptosis and alleviated inflammation and apoptosis by regulating the NF-κB, JNK, and Bcl-2/Bax signaling pathways.

scholarly journals Dual Control of Muscle Cell Survival by Distinct Growth Factor-Regulated Signaling Pathways

2000 ◽  
Vol 20 (9) ◽  
pp. 3256-3265 ◽  
Author(s):  
Margaret A. Lawlor ◽  
Xiuhong Feng ◽  
Daniel R. Everding ◽  
Kerry Sieger ◽  
Claire E. H. Stewart ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Survival ◽  
Signaling Pathways ◽  
Muscle Cell ◽  
Transient Transfection ◽  
Pi3 Kinase ◽  
Signal Transduction Pathways ◽  
Apoptotic Death ◽  
Igf I

ABSTRACT In addition to their ability to stimulate cell proliferation, polypeptide growth factors are able to maintain cell survival under conditions that otherwise lead to apoptotic death. Growth factors control cell viability through regulation of critical intracellular signal transduction pathways. We previously characterized C2 muscle cell lines that lacked endogenous expression of insulin-like growth factor II (IGF-II). These cells did not differentiate but underwent apoptotic death in low-serum differentiation medium. Death could be prevented by IGF analogues that activated the IGF-I receptor or by unrelated growth factors such as platelet-derived growth factor BB (PDGF-BB). Here we analyze the signaling pathways involved in growth factor-mediated myoblast survival. PDGF treatment caused sustained activation of extracellular-regulated kinases 1 and 2 (ERK1 and -2), while IGF-I only transiently induced these enzymes. Transient transfection of a constitutively active Mek1, a specific upstream activator of ERKs, maintained myoblast viability in the absence of growth factors, while inhibition of Mek1 by the drug UO126 blocked PDGF-mediated but not IGF-stimulated survival. Although both growth factors activated phosphatidylinositol 3-kinase (PI3-kinase) to similar extents, only IGF-I treatment led to sustained stimulation of its downstream kinase, Akt. Transient transfection of a constitutively active PI3-kinase or an inducible Akt promoted myoblast viability in the absence of growth factors, while inhibition of PI3-kinase activity by the drug LY294002 selectively blocked IGF- but not PDGF-mediated muscle cell survival. In aggregate, these observations demonstrate that distinct growth factor-regulated signaling pathways independently control myoblast survival. Since IGF action also stimulates muscle differentiation, these results suggest a means to regulate myogenesis through selective manipulation of different signal transduction pathways.

scholarly journals Permissive Roles of Phosphatidyl Inositol 3-Kinase and Akt in Skeletal Myocyte Maturation

2004 ◽  
Vol 15 (2) ◽  
pp. 497-505 ◽  
Author(s):  
Elizabeth M. Wilson ◽  
Jolana Tureckova ◽  
Peter Rotwein
Keyword(s):  
Growth Factors ◽  
Signaling Pathways ◽  
Transcriptional Activation ◽  
Muscle Development ◽  
Kinase Inhibitor ◽  
Troponin T ◽  
Phosphatidyl Inositol ◽  
Muscle Differentiation ◽  
Pi3 Kinase ◽  
Dominant Negative

Skeletal muscle differentiation, maturation, and regeneration are regulated by interactions between signaling pathways activated by hormones and growth factors, and intrinsic genetic programs controlled by myogenic transcription factors, including members of the MyoD and myocyte enhancer factor 2 (MEF2) families. Insulin-like growth factors (IGFs) play key roles in muscle development in the embryo, and in the maintenance and hypertrophy of mature muscle in the adult, but the precise signaling pathways responsible for these effects remain incompletely defined. To study mechanisms of IGF action in muscle, we have developed a mouse myoblast cell line termed C2BP5 that is dependent on activation of the IGF-I receptor and the phosphatidyl inositol 3-kinase (PI3-kinase)-Akt pathway for initiation of differentiation. Here, we show that differentiation of C2BP5 myoblasts could be induced in the absence of IGF action by recombinant adenoviruses expressing MyoD or myogenin, but it was reversibly impaired by the PI3-kinase inhibitor LY294002. Similar results were observed using a dominant-negative version of Akt, a key downstream component of PI3-kinase signaling, and also were seen in C3H 10T1/2 fibroblasts. Inhibition of PI3-kinase did not prevent accumulation of muscle differentiation-specific proteins (myogenin, troponin T, or myosin heavy chain), did not block transcriptional activation of E-box containing muscle reporter genes by MyoD or myogenin, and did not inhibit the expression or function of endogenous MEF2C or MEF2D. An adenovirus encoding active Akt could partially restore terminal differentiation of MyoD-expressing and LY294002-treated myoblasts, but the resultant myofibers contained fewer nuclei and were smaller and thinner than normal, indicating that another PI3-kinase-stimulated pathway in addition to Akt is required for full myocyte maturation. Our results support the idea that an IGF-regulated PI3-kinase pathway functions downstream of or in parallel with MyoD, myogenin, and MEF2 in muscle development to govern the late steps of differentiation that lead to multinucleated myotubes.

scholarly journals Forkhead Transcription Factor FKHR-L1 Modulates Cytokine-Dependent Transcriptional Regulation of p27KIP1

2000 ◽  
Vol 20 (24) ◽  
pp. 9138-9148 ◽  
Author(s):  
Pascale F. Dijkers ◽  
Rene H. Medema ◽  
Cornelieke Pals ◽  
Lolita Banerji ◽  
N. Shaun B. Thomas ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Cell Survival ◽  
Kinase Inhibitor ◽  
Ectopic Expression ◽  
Dependent Manner ◽  
Forkhead Transcription Factor ◽  
Protein Levels ◽  
Macrophage Colony ◽  
Null Mutant Mice

ABSTRACT Interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor regulate the survival, proliferation, and differentiation of hematopoietic lineages. Phosphatidylinositol 3-kinase (PI3K) has been implicated in the regulation of these processes. Here we investigate the molecular mechanism by which PI3K regulates cytokine-mediated proliferation and survival in the murine pre-B-cell line Ba/F3. IL-3 was found to repress the expression of the cyclin-dependent kinase inhibitor p27KIP1 through activation of PI3K, and this occurs at the level of transcription. This transcriptional regulation occurs through modulation of the forkhead transcription factor FKHR-L1, and IL-3 inhibited FKHR-L1 activity in a PI3K-dependent manner. We have generated Ba/F3 cell lines expressing a tamoxifen-inducible active FKHR-L1 mutant [FKHR-L1(A3):ER*]. Tamoxifen-mediated activation of FKHR-L1(A3):ER* resulted in a striking increase in p27KIP1 promoter activity and mRNA and protein levels as well as induction of the apoptotic program. The level of p27KIP1 appears to be critical in the regulation of cell survival since mere ectopic expression of p27KIP1 was sufficient to induce Ba/F3 apoptosis. Moreover, cell survival was increased in cytokine-starved bone marrow-derived stem cells from p27KIP1 null-mutant mice compared to that in cells from wild-type mice. Taken together, these observations indicate that inhibition of p27KIP1transcription through PI3K-induced FKHR-L1 phosphorylation provides a novel mechanism of regulating cytokine-mediated survival and proliferation.

scholarly journals Undernutrition Affects Cell Survival, Oxidative Stress, Ca2+ Handling and Signaling Pathways in Vas Deferens, Crippling Reproductive Capacity

PLoS ONE ◽  
2013 ◽  
Vol 8 (7) ◽  
pp. e69682 ◽  
Author(s):  
Humberto Muzi-Filho ◽  
Camila G. P. Bezerra ◽  
Alessandro M. Souza ◽  
Leonardo C. Boldrini ◽  
Christina M. Takiya ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Survival ◽  
Signaling Pathways ◽  
Vas Deferens ◽  
Reproductive Capacity

scholarly journals Ligation of the α2-macroglobulin signalling receptor on macrophages induces protein phosphorylation and an increase in cytosolic pH

1995 ◽  
Vol 309 (1) ◽  
pp. 151-158 ◽  
Author(s):  
U K Misra ◽  
G Gawdi ◽  
S V Pizzo
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factors ◽  
Protein Phosphorylation ◽  
Tyrosine Phosphorylation ◽  
Kinase Inhibitor ◽  
Density Lipoprotein ◽  
Ligand Concentration ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Cytosolic Ph

We have recently described an alpha 2-macroglobulin (alpha 2M) signalling receptor which is distinct from the low-density lipoprotein-related protein/alpha 2M receptor (LRP/alpha 2MR). Ligation of the macrophage signalling receptor by alpha 2M-methylamine stimulates production of several second messengers and involves a pertussis toxin-insensitive G-protein. We now report that binding of alpha 2M-methylamine, or the cloned M(r) = 20,000 receptor-binding fragment from rat alpha 1M, to macrophage alpha 2M signalling receptors induces protein phosphorylation. By use of a monoclonal antibody to phospholipase C gamma l (PLC gamma l) we were able to identify it as one target for protein phosphorylation. Phosphorylation was time and concentration dependent, being optimal at about 60 s of incubation and a 100-200 nM ligand concentration. By use of a second monoclonal antibody directed against phosphotyrosine, we were able to demonstrate that at least a portion of the label was incorporated into one or more tyrosine residues. PLC gamma l phosphorylation was then studied in membrane preparations at 4 degrees C in order to minimize serine or threonine modification. Preincubation of macrophage membranes with genistein, a tyrosine kinase inhibitor, drastically reduced phosphorylation of PLC gamma l. Receptor-associated protein, which blocks alpha 2M binding to LRP/alpha 2MR but not to the alpha 2M signalling receptor, had no effect on alpha 2M-methylamine-induced tyrosine phosphorylation of PLC gamma l. Binding of lactoferrin to LRP/alpha 2MR failed to induce phosphorylation of PLC gamma l, further supporting the hypothesis that the alpha 2M signalling receptor and LRP/alpha 2MR are distinct entities. Growth factors which induce tyrosine phosphorylation typically cause a rise in cytosolic pH. Binding of a2M-methylamine to macrophages also gradually increased the intracellular pH in a concentration-dependent manner, being optimal at a 200 nM ligand concentration. The increase in pH was amiloride sensitive. We propose that receptor-recognized forms of a2M may function like growth factors with regard to macrophage regulation.

Chikusetsu saponin V attenuates H2O2-induced oxidative stress in human neuroblastoma SH-SY5Y cells through Sirt1/PGC-1α/Mn-SOD signaling pathways

2016 ◽  
Vol 94 (9) ◽  
pp. 919-928 ◽  
Author(s):  
Jingzhi Wan ◽  
Lili Deng ◽  
Changcheng Zhang ◽  
Qin Yuan ◽  
Jing Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Signaling Pathways ◽  
Vital Role ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Human Neuroblastoma ◽  
Ros Accumulation ◽  
Antioxidative Effects ◽  
Dose Dependent

Oxidative stress plays a vital role in the pathogenesis of neurodegenerative diseases. Chikusetsu saponin V (CsV), the most abundant member of saponins from Panax japonicus (SPJ), has attracted increasing attention for its potential to treat neurodegenerative diseases. However, the mechanisms are unclear. Our study intended to investigate the antioxidative effects of CsV in human neuroblastoma SH-SY5Y cells. Our data showed that CsV attenuated H2O2-induced cytotoxicity, inhibited ROS accumulation, increased the activities of superoxide dismutase (SOD) and GSH, and increased mitochondrial membrane potential dose-dependently. Further exploration of the mechanisms showed that CsV exhibited these effects through increasing the activation of oxidative-stress-associated factors including Sirt1, PGC-1α, and Mn-SOD. Moreover, CsV inhibited H2O2-induced down-regulation of Bcl-2 and up-regulation of Bax in a dose-dependent manner and, thus, increased the ratio of Bcl-2/Bax. In conclusion, our study demonstrated that CsV exhibited neuroprotective effects possibly through Sirt1/PGC-1α/Mn-SOD signaling pathways.

scholarly journals Nox4 NADPH oxidase-derived reactive oxygen species, via endogenous carbon monoxide, promote survival of brain endothelial cells during TNF-α-induced apoptosis

2011 ◽  
Vol 300 (2) ◽  
pp. C256-C265 ◽  
Author(s):  
Shyamali Basuroy ◽  
Dilyara Tcheranova ◽  
Sujoy Bhattacharya ◽  
Charles W. Leffler ◽  
Helena Parfenova
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Nadph Oxidase ◽  
Cell Survival ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Tnf Α ◽  
Mapk Signaling Pathways

We investigated the role of reactive oxygen species (ROS) in promoting cell survival during oxidative stress induced by the inflammatory mediator tumor necrosis factor-α (TNF-α) in cerebral microvascular endothelial cells (CMVEC) from newborn piglets. Nox4 is the major isoform of NADPH oxidase responsible for TNF-α-induced oxidative stress and apoptosis in CMVEC. We present novel data that Nox4 NADPH oxidase-derived ROS also initiate a cell survival mechanism by increasing production of a gaseous antioxidant mediator carbon monoxide (CO) by constitutive heme oxygenase-2 (HO-2). TNF-α rapidly enhanced endogenous CO production in a superoxide- and NADPH oxidase-dependent manner in CMVEC with innate, but not with small interfering RNA (siRNA)-downregulated Nox4 activity. CORM-A1, a CO-releasing compound, inhibited Nox4-mediated ROS production and enhanced cell survival in TNF-α-challenged CMVEC. The ROS-induced CO-mediated survival mechanism requires functional interactions between the protein kinase B/Akt and extracellular signal-related kinase (ERK)/p38 MAPK signaling pathways activated by TNF-α. In Akt siRNA-transfected CMVEC and in cells with pharmacologically inhibited Akt, Erk1/2, and p38 mitogen-activated protein kinase (MAPK) activities, CORM-A1 was no longer capable of blocking Nox4 activation and apoptosis caused by TNF-α. Overall, Nox4 NADPH oxidase-derived ROS initiate both death and survival pathways in TNF-α-challenged CMVEC. The ROS-dependent cell survival pathway is mediated by an endogenous antioxidant CO, which inhibits Nox4 activation via a mechanism that includes Akt, ERK1/2, and p38 MAPK signaling pathways. The ability of CO to inhibit TNF-α-induced ERK1/2 and p38 MAPK activities in an Akt-dependent manner appears to be the key element in ROS-dependent survival of endothelial cells during TNF-α-mediated brain inflammatory disease.

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