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At least 1,513 records · Page 84Linked to original sources
PubMed2002

Prostaglandin E2 reinforces the activation of Ras signal pathway in lung adenocarcinoma cells via EP3.

Prostaglandin E2 (PGE2)-dependent effects on various cell responses are regulated by respective PGE2 receptors (EP1, EP2, EP3, EP4) expressing in target cells. Alveolar type II cell (a main progenitor cell of lung adenocarcinoma) expressed only EP4, while human lung adenocarcinoma cells (A549) expressed EP3 as well as EP4. An antagonistic effect of EP3 against EP4 through the modulation of cyclic AMP level is required for PGE2-mediated activation of Ras signal pathway in A549 cells. These results suggest that the expression of EP3 may be a critical factor for the PGE2-mediated activation of Ras signal pathway in A549 cells.

Adenocarcinoma↗
PubMed2001

Involvement of claudin-1 in the beta-catenin/Tcf signaling pathway and its frequent upregulation in human colorectal cancers.

Accumulation of beta-catenin in cytoplasm and nuclei is frequently observed in a wide variety of tumors arising, for example, in the colon, liver, uterus, or brain. In association with Tcf/LEF transcription factors, beta-catenin regulates expression of genes involved in the Wnt/wingless signaling pathway, but the precise mechanisms are unclear. Here we report evidence that the claudin-1 (CLDNI) gene is one of the genes regulated by beta-catenin. Not only did expression of CLDN1 decrease significantly in response to reduction of intracellular beta-catenin by adenovirus-mediated transfer of wild-type APC into the APC-deficient colon cancer cells, but also two putative Tcf4 binding elements in the 5' flanking region of CLDN1 were confirmed to be responsible for activating its transcription. We documented increased expression of CLDN1 in all 16 primary colorectal cancers we examined, compared with adjacent noncancerous mucosae. Furthermore, immunohistochemical staining demonstrated that claudin-1 was weakly stained at apical boarder of lateral membrane of noncancerous epithelial cells and that it was strongly stained at all cell-cell boundaries and in the cytoplasms of cancer cells. Our results imply that claudin-1 is involved in the beta-catenin-Tcf/LEF signaling pathway, and that increased expression of claudin-1 may have some role in colorectal tumorigenesis.

Claudin-1↗
PubMed2001

Intracellular Bax translocation after transient cerebral ischemia: implications for a role of the mitochondrial apoptotic signaling pathway in ischemic neuronal death.

Activation of terminal caspases such as caspase-3 plays an important role in the execution of neuronal cell death after transient cerebral ischemia. Although the precise mechanism by which terminal caspases are activated in ischemic neurons remains elusive, recent studies have postulated that the mitochondrial cell death-signaling pathway may participate in this process. The bcl-2 family member protein Bax is a potent proapoptotic molecule that, on translocation from cytosol to mitochondria, triggers the activation of terminal caspases by increasing mitochondrial membrane permeability and resulting in the release of apoptosis-promoting factors, including cytochrome c. In the present study, the role of intracellular Bax translocation in ischemic brain injury was investigated in a rat model of transient focal ischemia (30 minutes) and reperfusion (1 to 72 hours). Immunochemical studies revealed that transient ischemia induced a rapid translocation of Bax from cytosol to mitochondria in caudate neurons, with a temporal profile and regional distribution coinciding with the mitochondrial release of cytochrome c and caspase-9. Further, in postischemic caudate putamen in vivo and in isolated brain mitochondria in vitro, the authors found enhanced heterodimerization between Bax and the mitochondrial membrane permeabilization-related proteins adenine nucleotide translocator (ANT) and voltage-dependent anion channel. The ANT inhibitor bongkrekic acid prevented Bax and ANT interactions and inhibited Bax-triggered caspase-9 release from isolated brain mitochondria in vitro. Bongkrekic acid also offered significant neuroprotection against ischemia-induced caspase-3 and caspase-9 activation and cell death in the brain. These results strongly suggest that the Bax-mediated mitochondrial apoptotic signaling pathway may play an important role in ischemic neuronal injury.

Animals↗
PubMed1996

Halothane and isoflurane inhibit vasodilation due to constitutive but not inducible nitric oxide synthase. Implications for the site of anesthetic inhibition of the nitric oxide/guanylyl cyclase signaling pathway.

BACKGROUND: Inhalational anesthetics inhibit the nitric oxide-guanylyl cyclase signaling pathway, but the site of this inhibition is not yet clear. This study was designed to test the hypothesis that receptor activation or downstream signaling events leading to nitric oxide synthase activation are important sites for this inhibition by comparing the effect of anesthetics on vasodilation caused by the calcium-dependent constitutive endothelial nitric oxide synthase versus the calcium-independent inducible nitric oxide synthase. METHODS: Endothelium-intact or -denuded rat thoracic aorta rings preincubated with or without lipopolysaccharide were mounted for isometric tension measurement, constricted with phenylephrine, then relaxed with methacholine in the presence or absence of halothane (1-3%) or isoflurane (1-3%). The cyclic guanosine 3,5-monophosphate content in the endothelium-denuded rings preincubated with or without lipopolysaccharide in the presence or absence of 3% halothane or 3% isoflurane was quantified by radioimmunoassay. The activity of partially purified inducible nitric oxide synthase from activated mouse macrophage was assayed in the presence or absence of halothane (1-4%) or isoflurane (1-5%) by the conversion of 3H-L-arginine to 3H-L-citrulline. RESULTS: Halothane and isoflurane inhibited methacholine-stimulated, nitric oxide-mediated vasorelaxation in endothelium-intact aortic rings. Neither halothane nor isoflurane affected the vasorelaxation caused by basal endothelial nitric oxide synthase or inducible nitric oxide synthase activity. Neither anesthetic altered the cyclic guanosine 3,5-monophosphate increase caused by inducible nitric oxide synthase in the lipopolysaccharide-treated rings. CONCLUSIONS: The results demonstrated that halothane and isoflurane inhibit only receptor/calcium-activated nitric oxide synthase action and that direct inhibition of nitric oxide synthase, soluble guanylyl cyclase, or an interaction with nitric oxide are not responsible for anesthetic inhibition of endothelium-dependent vasorelaxation.

Anesthetics, Inhalation↗
PubMed2002

The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways.

Human cartilage glycoprotein 39 (HC-gp39) is a glycoprotein secreted by articular chondrocytes, synoviocytes and macrophages. Increased levels of HC-gp39 have been demonstrated in synovial fluids of patients with rheumatoid or osteoarthritis. The increased secretion of HC-gp39 under physiological and pathological conditions with elevated connective-tissue turnover suggests its involvement in the homoeostasis of these tissues. We report here that HC-gp39 promotes the growth of human synovial cells as well as skin and fetal lung fibroblasts. A dose-dependent growth stimulation was observed when each of the fibroblastic cell lines was exposed to HC-gp39 in a concentration range from 0.1 to 2 nM, which is similar to the effective dose of the well-characterized mitogen, insulin-like growth factor-1. At suboptimal concentrations, the two growth factors work in a synergistic fashion. The use of selective inhibitors of the mitogen-activated protein kinase and the protein kinase B (AKT) signalling pathways indicates that both are involved in mediating the mitogenic response to HC-gp39. Phosphorylation of both extracellular signal-regulated kinases 1/2 and AKT occurred in a dose- and time-dependent fashion upon addition of HC-gp39. Activation of these signalling pathways could also be demonstrated in human chondrocytes. Thus HC-gp39 initiates a signalling cascade in connective-tissue cells which leads to increased cell proliferation, suggesting that this protein could play a major role in the pathological conditions leading to tissue fibrosis.

Adipokines↗
PubMed1999

Mouse semaphorin H induces PC12 cell neurite outgrowth activating Ras-mitogen-activated protein kinase signaling pathway via Ca(2+) influx.

We recently showed that mouse semaphorin H (MSH), a secreted semaphorin molecule, acts as a chemorepulsive factor on sensory neurites. In this study, we found for the first time that MSH induces neurite outgrowth in PC12 cells in a dose-dependent manner. Comparison of Ras-mitogen-activated protein kinase (MAPK) signaling pathways between MSH and nerve growth factor (NGF) revealed that these pathways are crucial for MSH action as well as NGF. K-252a, an inhibitor of tyrosine autophosphorylation of tyrosine kinase receptors (Trks), did not inhibit the action of MSH, suggesting that MSH action occurs via a different receptor than NGF. L- and N-types of voltage-dependent Ca(2+) channel blockers, diltiazem and omega-conotoxin, inhibited MSH-induced neurite outgrowth and MAPK phosphorylation in a Ca(2+)-dependent manner. A transient elevation in intracellular Ca(2+) level was observed upon MSH stimulation. These findings suggest that extracellular Ca(2+) influx, followed by activation of the Ras-MAPK signaling pathway, is required for MSH induced PC12 cell neurite outgrowth.

3T3 Cells↗
PubMedDate not supplied

Genetic analysis of interferon and other mammalian signaling pathways.

Systematic forward genetics, so powerful for analyzing pathways in haploid organisms, has contributed much less to our understanding of diploid mammalian cells. With Ian Kerr, we have used regulated expression of selectable markers in heavily mutagenized cells to isolate mutant mammalian cell lines defective in eight different proteins required for interferon signaling. These cells have been valuable in studying the roles of the deleted Janus Kinase (JAK), signal transducer and activator of transcription (STAT), and receptor proteins in interferon and other signaling pathways. Mutant cells defective in the induction of class II major histocompatibility complex (MHC) antigens by interferon-gamma or in repressing interferon-regulated genes have also been obtained. More recently, mutant cells unresponsive to double-stranded RNA, tumor necrosis factor alpha (TNF-alpha), or interleukin-1 (IL-1) have been isolated and characterized and a mutant line defective in expressing the tumor suppressor protein p53 has also been obtained. Systematic forward genetics can now be applied more easily to mammalian cells, to help elucidate signaling pathways.

Animals↗
PubMed1998

Optimal erythropoietin expression in human hepatoma cell lines requires activation of multiple signalling pathways.

Hypoxia is thought to be a common precursor of coronary artery disease and malignant tumors, both diseases representing the leading causes of death in industrial nations. So far, investigations of oxygen-regulated erythropoietin (EPO) gene expression in the human hepatoma cell lines Hep3B and HepG2 allowed many important insights into the mechanisms of oxygen-sensing, signalling and regulation of an increasing number of oxygen-responsive genes. To differentiate the various signalling pathways involved in EPO production by these two cell lines, we examined several factors that positively influenced EPO expression. The results demonstrate a keen differential effect of cell density and oxygen concentration on EPO induction in Hep3B compared to HepG2 cells. Using optimized cell culture conditions, EPO production rates as high as 1 U EPO per 10(6) Hep3B cells in 24 h could be achieved. We also found a moderate but reproducible positive effect of CoCl2 on hypoxia-induced EPO expression in Hep3B but a negative CoCl2 effect on hypoxic induction in HepG2 cells. CoCl2 inhibited cell growth in a concentration-dependent manner. Interleukin-6 was synergistic with hypoxia on EPO induction in Hep3B as well as HepG2 cells, and dexamethasone enhanced this effect in Hep3B but not in HepG2 cells. The moderate CoCl2-dependent increase of EPO production observed in hypoxic Hep3B cells might indicate that CoCl2 and hypoxia do not necessarily act via, identical signalling pathways.

Carcinoma, Hepatocellular↗
PubMed2004

Crosstalk of hypoxia-mediated signaling pathways in upregulating plasminogen activator inhibitor-1 expression in keloid fibroblasts.

Keloids are skin fibrotic conditions characterized by an excess accumulation of extracellular matrix (ECM) components secondary to trauma or surgical injuries. Previous studies have shown that plasminogen activator inhibitor-1 (PAI-1) can be upregulated by hypoxia and may contribute to keloid pathogenesis. In this study we investigate the signaling mechanisms involved in hypoxia-mediated PAI-1 expression in keloid fibroblasts. Using Northern and Western blot analysis, transient transfections, and pharmacological agents, we demonstrate that hypoxia-induced upregulation of PAI-1 expression is mainly controlled by hypoxia inducible factors-1alpha (HIF-1alpha) and that hypoxia leads to a rapid and transient activation of phosphatidylinositol-3-kinase/Akt (PI3-K/Akt) and extracellular signal-regulated kinases 1/2 (ERK1/2). Treatment of cells with PI-3K/Akt inhibitor (LY294002) and tyrosine protein kinase inhibitor (genistein) significantly attenuated hypoxia-induced PAI-1 mRNA and protein expression as well as promoter activation, apparently via an inhibition of the hypoxia-induced stabilization of HIF-1alpha protein, attenuation of the steady-state level of HIF-1alpha mRNA, and its DNA-binding activity. Even though disruption of ERK1/2 signaling pathway by PD98059 abolished hypoxia-induced PAI-1 promoter activation and mRNA/protein expression in keloid fibroblasts, it did not inhibit the hypoxia-mediated stabilization of HIF-1alpha protein and the steady-state level of HIF-1alpha mRNA nor its DNA binding activity. Our findings suggest that a combination of several signaling pathways, including ERK1/2, PI3-K/Akt, and protein tyrosine kinases (PTKs), may contribute to the hypoxia-mediated induction of PAI-1 expression via activation of HIF-1alpha in keloid fibroblasts.

Blotting, Northern↗
PubMed1996

Differential effects of platelet-derived growth factor isotypes on human smooth muscle cell proliferation and migration are mediated by distinct signaling pathways.

BACKGROUND: Platelet-derived growth factor (PDGF) is a potent mitogen and chemoattractant for vascular smooth muscle cells (SMCs). Three isotypes of PDGF (BB, AB, and AA) have been identified; each of these isotypes may have differing effects on the behaviour of vascular SMCs. In this study we evaluated the influence of PDGF isotypes on proliferation and migration of human venous SMCs and explored the signaling pathways through which these effects are mediated. METHODS: Proliferation was measured by a 72-hour assay of cell number, and migration was evaluated by a 4-hour microchemotaxis assay. The effects of PDGF isotypes on the activities of the signaling proteins mitogen-activated protein kinase (MAP-K), p 125 focal adhesion kinase (p125FAK), and tensin were measured by immunoprecipitation of these proteins and subsequent phosphorylation on myelin basic protein (in MAP-K) and Western blotting with antiphosphotyrosine (in tensin and p125FAK). RESULTS: All three isotypes stimulated SMC proliferation (PDGF-BB > AB > AA). PDGF-BB and -AB, but not -AA, stimulated chemotaxis. All three isotypes activated MAP-K with an intensity that corresponded to their proliferative effects. PDGF-BB and -AB tyrosine phosphorylated tensin and p125FAK, whereas PDGF-AA had no effect on either of these proteins. CONCLUSIONS: For human vascular SMCs the physiologic effects and the signaling pathways that mediate these effects are specific for each of the three PDGF isotypes. These data also suggest an association between MAP-K and SMC proliferation and between the proteins, p125FAK and tensin, and migration.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2003

Cdk2-dependent phosphorylation of the NF-Y transcription factor and its involvement in the p53-p21 signaling pathway.

Recent studies have suggested that the NF-Y transcription factor is involved in transcription repression of the cell cycle regulatory genes in a response to p53 induction or DNA damage. Here we demonstrate the cdk2-dependent phosphorylation of NF-Y and its involvement in transcription repression by the p53-p21 signaling pathway. Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. Consistently, YA-aa inhibits transcription activation of a NF-Y target promoter, cdc2, by cdk2. These results facilitate the elucidation of the regulatory mechanisms of cell cycle progression involving the p21-cdk2-NF-Y signaling pathway.

Amino Acid Sequence↗
PubMed2004

Study of the effects of interferon a on several human hepatoma cell lines: analysis of the signalling pathway of the cytokine and of its effects on apoptosis and cell proliferation.

BACKGROUND: Interferon alpha (IFNalpha), currently used for the treatment of chronic viral hepatitis, is also known to prevent the development of hepatocellular carcinoma (HCC), the mechanism of this action being still debatable. AIMS: To study thoroughly in human hepatoma cell lines (HHL)--Hep3B, HepG2, HuH7, SKHep1, and Chang-Liver--submitted to rhIFNalpha, the signalling pathway of IFNalpha, the binding activity of the cytokine on specific gamma-activated sequence (GAS) and interferon-stimulated regulatory element (ISRE) nuclear sequences, and its effects on apoptosis and cell proliferation. METHODS: The behaviour of signal transducer and activator of transcription (STAT)1, STAT2, p48(IRF9) and the binding of nuclear proteins were investigated by immunoblot and electro-mobility shift assay. Expression of some IFNalpha-dependent proteins--p21/(WAF1), inducible nitric oxide synthase, IRF1 and 2--were studied by immunoblot. Apoptosis and the cell cycle were studied by morphological and biochemical methods. RESULTS: Transduction of INFalpha was unaltered, although there were some variations in the different HHL. Nuclear protein binding to GAS or ISRE showed that ISRE was mainly involved. Apoptosis did not occur. The cell cycle was slightly modified in HuH7. Three GAS- and/or ISRE-dependent proteins increased, suggesting that IFNalpha may have some biological effects on HHL. CONCLUSIONS: The IFNalpha signalling pathway is functional in several HHL, but the cytokine has no apoptotic effect and a moderate anti-proliferative effect. This suggests that the preventive role of IFNalpha on HCC cannot be explained by an apoptotic and/or an anti-proliferative effect, but possibly by its action on several specific nuclear sequences that protect liver cells from transformation.

Apoptosis↗
PubMed2006

In-situ demonstration of mitogen-activated protein kinase Erk 1/2 signalling pathway in contagious respiratory tumours of sheep and goats.

Ovine pulmonary adenocarcinoma (OPA) and enzootic nasal adenocarcinoma (ENA) are two contagious neoplastic diseases of secretory epithelial cells in the respiratory system of sheep and goats. Jaagsiekte sheep retrovirus (JSRV) is the aetiological agent of OPA, and enzootic nasal tumour virus (ENTV) is associated with ENA. The genomes of these retroviruses do not contain known oncogenes but products of the env gene are important in the generation of transforming stimuli. However, the cell signalling pathways activated in vivo are not completely understood. This study was based on the use of activation stage antibodies specifically detecting proteins of the extracellular signal regulated kinase Erk 1/2 cell signalling pathway and transcription factors. Tissue sections were collected from four natural cases of OPA, four experimentally induced OPA tumours, four ENA tumours in sheep, four ENA tumours in goats, two normal sheep lungs and two lungs with chronic inflammation. Routine immunohistochemical procedures with phosphorylation stage-specific antibodies were carried out. Representative proteins of the Erk1/2 pathway (Raf-1, Mek1/2 and p44/42MAPK) were activated in natural cases of OPA and ENA in sheep and goats and also in experimentally induced OPA. Transcription factors 90Rsk and Elk-1 were activated in OPA and ENA tumours. However, c-Myc was activated only in OPA tumours. In contagious respiratory neoplasms of sheep and goats the Erk1/2 pathway appears to be important for the in-vivo generation of the transforming stimuli.

Adenocarcinoma↗
PubMed1999

Insulin-like growth factor signaling pathways in rat hepatic stellate cells: importance for deoxyribonucleic acid synthesis and hepatocyte growth factor production.

It has been shown recently that insulin-like growth factor 1 (IGF-1) increases both DNA synthesis and hepatocyte growth factor (HGF) production in cultured hepatic stellate cells. In this study, we used selective blockers to investigate crucial signaling pathways for these effects of IGF-1 in cultured rat hepatic stellate cells. Both LY 294002 [a phosphatidylinositol 3-kinase (PI3-K) inhibitor], and rapamycin [a blocker of activation of the serine/threonine p70 S6 kinase (p70S6K), a molecule downstream from PI3-K] completely reversed the IGF-1-induced stimulation of DNA synthesis. Mitogen-activated protein kinase (MAPK) inhibition by PD 98059 had a less pronounced suppressory effect, although the used PD 98059 dose was fully effective in inhibiting MAPK phosphorylation. Both LY 294002 and PD 98059 lowered the IGF-1-induced increase of HGF in the medium by about 40%, but LY 294002 was 10 times more potent than PD 98059. Inhibition of p70S6K activation by rapamycin blocked IGF-1-induced DNA synthesis but not the increase in HGF. In conclusion, PI3-K (and, to some extent, MAPK) signaling pathways seem to be important for IGF-1-stimulated DNA synthesis and HGF production. DNA synthesis also seems to be dependent on rapamycin-sensitive activation of the PI3-K effector p70S6K.

Animals↗
PubMed2005

The role of MAPK signal pathways during Francisella tularensis LVS infection-induced apoptosis in murine macrophages.

Francisella tularensis is a highly virulent intracellular pathogen responsible for tularemia. This bacterium is capable of infecting many mammalian species and various cell types, but little is known about the mechanisms of survival and interactions with host cells. We examined the number of infected host cells, cytotoxicity and the role of apoptosis or necrosis in infection-induced cell death. Our results demonstrate that F. tularensis LVS induces apoptosis of infected macrophages within 10 h. At later time points we were also able to detect a dramatic increase in the proportion of necrotic macrophages. We investigated the signalling pathways involved in infection-induced cell death by analysing three mitogen-activated protein kinase (MAPK) pathways that are known to be activated by LPS stimulation; p42/p44 MAPK (Erk1/2), transcription factor c-Jun and p38 MAPK. We identified post-translational activation of both p42 MAPK and p44 MAPK by phosphorylation at threonine and tyrosine residues after infection. Furthermore, treatment of infected cells with MEK1/2 inhibitors abrogated phosphorylation of p42/p44 MAPK and inhibited macrophage apoptosis and necrosis after infection. In contrast, phosphorylation and kinase activity of p38 MAPK was significantly lower in F. tularensis-infected cells, and inhibition of p38 MAPK activity induced apoptosis in uninfected cells. When we monitored JNK-dependent phosphorylation of the transcription factor c-Jun, we did not observe any reactivity with either SAPK/JNK or phospho-SAPK/JNK antibodies at any time point. In conclusion, we demonstrate that F. tularensis LVS infection induces macrophage apoptosis. This process requires activation of the p42/p44 MAPK pathway and is associated with reduced p38 MAPK activity, indicating that infection-induced cell death can be caused by perturbation of these two signalling pathways.

Animals↗
PubMed2006

Butylated hydroxyanisole regulates ARE-mediated gene expression via Nrf2 coupled with ERK and JNK signaling pathway in HepG2 cells.

Many natural and synthetic cancer chemopreventive compounds are potent inducers of phase II detoxifying and antioxidant stress responsive genes. The phase II/antioxidant gene expression plays critical role in chemoprevention of carcinogenesis. The antioxidant responsive element (ARE), located on many phase II/antioxidant genes, binds with the transcription factor Nrf2, and is required for the activation of these phase II/antioxidant gene expression induced by many natural and synthetic cancer chemopreventive compounds. In this study, we investigated the potential roles of extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) in the regulation of butylated hydroxyanisole (BHA)-induced and Nrf2-dependent ARE transcriptional activity and ARE-mediated endogenous heme oxygenase-1 (HO-1) protein expression in HepG2 cells. ARE transcriptional activity and HO-1 protein expression were increased dose dependently after treatment with BHA in HepG2 cells. Dose-response and time-course experiments showed that BHA increased the accumulation of Nrf2, and concomitantly decreased the protein level of Keap1. We next examined the phosphorylation of the MAPKs, and found that BHA significantly increased the phosphorylation levels of ERK1/2 and JNK1/2. Importantly BHA-induced ARE transcriptional activity was attenuated by the inhibition of ERK and JNK signaling using biochemical inhibitors and their dominant-negative mutants. Using confocal microscopy technique, treatment with BHA showed the release of Nrf2 sequestered by Keap1 in the cytosol, and that Nrf2 translocated into the nucleus. Importantly, cDNA transfections of ERK and JNK signaling pathways similarly released Nrf2 from Keap1 cytosolic sequestration and translocating Nrf2 into the nucleus. Taken together, these results strongly suggested that ERK and JNK signaling pathways played important and positive roles in BHA-induced and Nrf2-dependent regulation of ARE-mediated gene expression, as well as the nuclear translocation of Nrf2 in HepG2 cells.

Blotting, Western↗
PubMed1995

The involvement of metabotropic glutamate receptors and their intracellular signalling pathways in sustained nociceptive transmission in rat dorsal horn neurons.

The excitatory responses of individual dorsal horn neurons to cutaneous brush, repeated application of the C-fibre-selective chemical algogen, mustard oil, or to ionophoretic (1S,3R)-ACPD [a metabotropic glutamate receptor (mGluR) agonist] were monitored by extracellular recording. We have previously shown that the responses of dorsal horn neurons to mustard oil are inhibited by several selective antagonists of mGluRs. Effects of ionophoresis of the mGluR antagonists (R,S)-CHPG and L-AP3 and a range of selective inhibitors of intracellular signalling pathways were examined on evoked responses here. The results suggest that protein kinase C, phospholipase A2 and perhaps Ca2+/calmodulin kinase II play a role in mediating the sustained elevated activity of dorsal horn neurons that is incrementally elicited by repeated application of mustard oil, but probably make little contribution to sustained brush-evoked activity. Concurrence in the sensitivity of mustard oil- and (1S,3R)-ACPD-evoked activity to (R,S)-CHPG, L-AP3 and to inhibitors of intracellular signalling pathways, suggests that mGluRs are an important origin of these intracellular signals required for sustained nociception.

Animals↗
PubMed2003

HIV-1 Nef triggers Vav-mediated signaling pathway leading to functional and morphological differentiation of dendritic cells.

The accessory HIV-1 Nef protein plays a key role in AIDS pathogenesis. We recently demonstrated that exogenous Nef triggers phenotypic and functional differentiation of immature dendritic cells (DCs). Here we investigated whether the Nef-induced DC differentiation occurs with morphological remodeling and have focused on the interference of Nef in the signaling pathways that regulates DC maturation. We found that exogenous Nef enters immature DCs, promoting their functional and morphological differentiation. Specifically, Nef promotes interleukin (IL) -12 release, which closely fits with nuclear factor (NF) -kappaB activation. Nef induces rearrangement of actin microfilaments, leading to uropod and ruffle formation. Moreover, Nef increases the capacity of DCs to form clusters with allogeneic CD4+ T cells, improving immunological synapse formation. Searching for molecules involved in Nef-triggered signaling pathways driving the DC maturation, we found that Nef targets Vav and promotes its tyrosine phosphorylation, associated with its nucleus-to-cytoplasm redistribution. This has a direct effect on Vav guanine nucleotide exchange factor activity for the small GTPase Rac1. We hypothesize that targeting Vav, Nef modulates both early signaling events (such as cytoskeletal rearrangement) and delayed responses (such as transcriptional regulation), promoting DC differentiation. Our results highlight how Nef may enhance T lymphocyte activation, thus fostering virus dissemination, manipulating the DC arm of the immune response.

Actin Cytoskeleton↗