Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to elucidate the signalling pathways involved in the cytokine-activated inducible nitric oxide synthase (iNOS) response in a human kidney epithelial cell line, A498. Unstimulated cells did not express iNOS. Exposure of A498 cells to a cytokine mixture consisting of interferon gamma, interleukin-1 beta and tumor necrosis factor-alpha (TNF-alpha) increased nitrite production, iNOS mRNA and protein expression. Pharmacological inhibition of tyrosine kinases, including janus kinase (JAK2), and protein kinase C (PKC) inhibited cytokine-mediated nitrite production and iNOS protein expression. The involvement of mitogen-activated protein kinases (MAPKs) was investigated. Inhibition of p38 MAPK, but not of an upstream activator of extracellular signal-regulated kinase (ERK), caused a decrease in iNOS expression and nitrite production in response to cytokines. Electrophoretic mobility shift assay of nuclear extract from cytokine-stimulated cells demonstrated a pronounced binding to a nuclear factor kappa B (NF-kappa B) sequence present in the human iNOS promoter. Furthermore, the NF-kappa B inhibitor pyrrolidinedithiocarbamate (PDTC) decreased cytokine-activated iNOS protein expression and nitrite production. The present study has demonstrated that cytokine-stimulated iNOS expression in human kidney epithelial cells involves activation of tyrosine kinases, including JAK2, PKC, p38 MAPK and NF-kappa B.
...
PMID:Signalling pathways regulating inducible nitric oxide synthase expression in human kidney epithelial cells. 1278 81

Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent chloride channel in epithelial cells; recently, we identified it in mast cells. Previous work that we confirmed showed that interferon gamma (IFNgamma) down-regulated CFTR expression in epithelial cells (T84), but by contrast, we found that IFNgamma up-regulated CFTR mRNA and protein expression in rat and human mast cells. IFNgamma up-regulation of CFTR in mast cells was inhibited by p38 and extracellular signal-regulated kinase (ERK) kinase inhibitors but not a Janus tyrosine kinase (JAK)2 inhibitor, whereas in T84 cells IFNgamma-mediated down-regulation of CFTR was JAK2-dependent and ERK- and p38-independent. Furthermore, IFNgamma down-regulation of CFTR in T84 epithelial cells was STAT1-dependent, but up-regulation of CFTR in mast cells was STAT1-independent. Thus, differential regulatory pathways of CFTR expression in mast cells and epithelial cells exist that depend upon either p38/ERK or JAK/STAT pathways, respectively. Surprisingly, IFNgamma treatment of mast cells inhibited Cl(-) efflux, in contrast to up-regulation of CFTR/mRNA and protein expression. However, down-regulation of Cl(-) flux correlated with IFNgamma-mediated inhibition of mediator secretion. This and other work suggests that the effect of IFNgamma on CFTR expression in mast cells is important for their function.
...
PMID:Differential regulation of cystic fibrosis transmembrane conductance regulator by interferon gamma in mast cells and epithelial cells. 1605 99

Macrophage-targeted photodynamic therapy (PDT) may have applications in the selective killing of cells involved in atherosclerosis, inflammation and tumor. We have previously shown that a conjugate between the photosensitizer chlorin(e6) (ce6) and maleylated bovine serum albumin (BSA-mal) gives highly selective targeting to macrophages. In this report we examine the effect of macrophage activation and scavenger receptor class A (SRA) expression on this targeting in two murine macrophage tumor cell lines (RAW264.7 and P388D1) and a control murine mammary sarcoma cell line (EMT-6). Cells were pretreated with interferon gamma (IFNgamma) and/or lipopolysaccharide (LPS) followed byBSA-ce6-mal addition, and SRA expression, tumor necrosis factor alpha (TNFalpha) release, conjugate uptake and PDT killing were measured. Both macrophage cell lines expressed SRA and took up conjugate specifically in an SRA-dependent manner, but differences were observed in their response to activation. RAW264.7 expressed increasingly more SRA and took up increasingly more BSA-ce6-mal in response to IFNgamma, LPS, and IFNgamma+LPS, respectively. The PDT killing did not follow the same pattern as the uptake of the photosensitizer. The increase in uptake in the IFNgamma treated cells did not lead to an increase in PDT killing, while stimulation with LPS or IFNgamma + LPS resulted in a significant protection against PDT, despite a significant increase in photosensitizer uptake. P388D1 was responsive to neither IFNgamma, nor to LPS, or to IFNgamma +LPS with respect to SRA expression, conjugate uptake, and PDT killing. These data may have implications for the use of PDT to target physiologically undesirable macrophage subtypes implicated in disease, and on how manipulation of the activation status of the macrophage will influence the PDT effect.
...
PMID:Macrophage-targeted photodynamic therapy: scavenger receptor expression and activation state. 1616 23

Thyroid-associated ophthalmopathy (TAO) is an autoimmune component of Graves' disease characterized by intense inflammation in the setting of volume expansion. At the heart of orbital susceptibility to Graves' disease appears to be the peculiar phenotype of orbital fibroblasts that, when activated by IL-1beta and other proinflammatory cytokines, produce excess prostaglandin E2 (PGE2) and hyaluronan. T helper type 1 (Th1) cytokines predominate early in TAO, whereas Th2 cytokines are more abundant later. It is currently unknown whether this transition might promote changes in tissue reactivity associated with disease progression. We report here that interferon-gamma and IL-4, representative of these respective classes of cytokines, attenuate IL-1beta-provoked PGE2 production. This down-regulation is mediated by blocking the induction of prostaglandin endoperoxide H synthase-2 (PGHS-2), the inflammatory cyclooxygenase. The mechanism involves blockade by IL-4 and interferon-gamma of the IL-1beta-dependent activation of PGHS-2 gene promoter activity. In addition, interferon gamma inhibits IL-1beta-provoked PGHS-2 mRNA stability. The actions of interferon-gamma and IL-4 are mediated through the Janus kinase 2/signal transducer and activator of transcription signaling pathway and could be abolished by treating with AG490, a specific inhibitor of Janus kinase 2. In contrast, the up-regulation of hyaluronan synthesis by IL-1beta is enhanced by either IL-4 or interferon-gamma. The latter two cytokines enhance the induction by IL-1beta of hyaluronan synthase-2 expression. These unexpected findings indicate that the Th1-->Th2 cytokine transition exerts equivalent influence on PGE2 and hyaluronan production as TAO progresses from early to late stage.
...
PMID:T helper type 1 and type 2 cytokines exert divergent influence on the induction of prostaglandin E2 and hyaluronan synthesis by interleukin-1beta in orbital fibroblasts: implications for the pathogenesis of thyroid-associated ophthalmopathy. 1636 40

The biological effects of interferon gamma (IFNgamma) are mediated by interferon-stimulated genes (ISGs), many of which are activated downstream of Janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling. Herein we have shown that IFNgamma rapidly activated AP-1 DNA binding that required c-Jun but was independent of JAK1 and STAT1. IFNgamma-induced c-Jun phosphorylation and AP-1 DNA binding required the MEK1/2 and ERK1/2 signaling pathways, whereas the JNK1/2 and p38 mitogen-activated protein kinase pathways were dispensable. The induction of several ISGs, including ifi-205 and iNOS, was impaired in IFNgamma-treated c-Jun-/- cells, but others, such as IP-10 and SOCS3, were unaffected, and chromatin immunoprecipitation demonstrated that c-Jun binds to the iNOS promoter following treatment with IFNgamma. Thus, IFNgamma induced JAK1- and STAT1-independent activation of the ERK mitogen-activated protein kinase pathway, phosphorylation of c-Jun, and activation of AP-1 DNA binding, which are important for the induction of a subset of ISGs. This represents a novel signal transduction pathway induced by IFNgamma that proceeds in parallel with conventional JAK/STAT signaling to activate ISGs.
...
PMID:A novel c-Jun-dependent signal transduction pathway necessary for the transcriptional activation of interferon gamma response genes. 1710 33

The present report provides evidence that, in A431 cells, interferon gamma (IFNgamma) induces the rapid (within 5 min), and reversible, tyrosine phosphorylation of the epidermal growth factor receptor (EGFR). IFNgamma-induced EGFR transactivation requires EGFR kinase activity, as well as activity of the Src-family tyrosine kinases and JAK2. Here, we show that IFNgamma-induced STAT1 activation in A431 and HeLa cells partially depends on the kinase activity of both EGFR and Src. Furthermore, in these cells, EGFR kinase activity is essential for IFNgamma-induced ERK1,2 activation. This study is the first to demonstrate that EGFR is implicated in IFNgamma-dependent signaling pathways.
...
PMID:Interferon gamma-dependent transactivation of epidermal growth factor receptor. 1736 40

Exenatide (Ex-4) is an antidiabetic drug that acts through the glucagon-like peptide 1 receptor and has recently been approved for the treatment of type 2 diabetes mellitus. Ex-4 also has been shown to affect beta cell gene expression and increase beta cell mass in rodent models of type 1 diabetes mellitus, but the mechanisms are not fully understood. We therefore analyzed the pathways affected by Ex-4 in human islets by using oligonucleotide microarrays and the PathwayStudio software (Ariadne Genomics, Rockville, MD). We identified the JAK1-STAT1 pathway as a novel target of Ex-4 and confirmed the Ex-4-mediated down-regulation of JAK1 and STAT1 by quantitative reverse transcription-polymerase chain reaction in human islets and INS-1 cells. JAK1-STAT1 is the major signaling pathway mediating the interferon gamma effects on beta cell apoptosis in type 1 diabetes mellitus. Thus, these findings suggest that Ex-4 treatment may also be beneficial in type 1 diabetes mellitus, where it may help protect beta cells from cytokine-induced cell death by inhibiting JAK1-STAT1.
...
PMID:Exenatide blocks JAK1-STAT1 in pancreatic beta cells. 1757 Feb 52

Individuals with impaired cell mediated immunity exhibit increased susceptibility to infections caused by poorly pathogenic mycobacteria (non-tuberculous mycobacteria and BCG), as well as salmonella species. However, these infections may also occur in a disseminated, fatal form, sometimes with a familial distribution, in the absence of any recognised primary or secondary immunodeficiency. Genetic analysis of affected families has defined mutations in seven different genes participating in the interleukin 12 (IL12) dependent, high output interferon gamma (IFNgamma) pathway. The first category of defect is mutations in the IFNgammaR1 or R2 genes, resulting in defective expression or function of the IFNgamma receptor. The second category of mutations abrogates the cell surface expression IL12Rbeta1gene, resulting in the inability to respond to IL12. The third category of defect is the inability to produce IL12, due to deletion within the gene coding for the inducible chain of IL12 (IL12-p40). Patients with X-linked recessive mutations of the gene encoding the NFkappaB essential modulator may also develop mycobacterial infections, although they usually have a more complex phenotype and are susceptible to a broad spectrum of pathogens. Mutations of the gene encoding the signal transducing molecule STAT1, which impairs the ability to respond to IFNgamma, and mutations of the gene encoding TYK2 (which is associated with a failure to respond to IL12), are both rare genetic defects predisposing to mycobacterial infections. This review summarises the clinical spectrum seen in this group of patients and indicates a strategy for the identification of putative genetic defects in the type-1 cytokine pathway.
...
PMID:Genetically determined susceptibility to mycobacterial infection. 1832 15

Interferon gamma (IFNgamma) is a highly pleotropic pro-inflammatory and anti-viral cytokine that mediates its effects by binding to a receptor complex composed of interferon gamma receptors 1 and 2 (IFNGR1 and IFNGR2). Using gene synteny analysis, we identified a distinct isoform of the zebrafish IFNGR1. The two zebrafish IFNGR1 called here IFNGR1-1 and IFNGR1-2 were used to identify the respective cDNA sequences of the goldfish IFNGR1-1 and IFNGR1-2. Analysis of protein sequences revealed that all fish IFNGR1 species have potential JAK1 and STAT1 docking sites. Phylogenetically, teleost IFNGR1 proteins grouped separately from those of higher vertebrates. Q-PCR analysis revealed that while the constitutive mRNA levels of the two zebrafish IFNGR1 isoforms were comparable in different tissues examined, the goldfish IFNGR1-1 tissue expression was substantially higher than that of IFNGR1-2. Q-PCR analysis of goldfish immune cell populations revealed highest expression of both receptor isoforms in monocytes. Incubation of goldfish macrophages with recombinant goldfish IFNgamma2 (rgIFNgamma2) up-regulated expression of both IFNGR1-1 and IFNGR1-2, while treatment of cells with rgTNFalpha2 only increased the expression of IFNGR1-1. Treatment with rgTGFbeta resulted in more modest increases in expression of both receptor isoforms only after prolonged treatment. In vitro binding studies indicated that rgIFNGR1-1 bound to rgIFNgamma1 but not rgIFNgamma2, while the rgIFNGR1-2 bound to rgIFNgamma2. Thus, unlike mammals that have a single IFNGR1, cyprinid fish have two distinct IFNGR1 isoforms that preferentially bind corresponding ligands, IFNgamma1 and IFNgamma2, respectively, suggesting that the type II interferon system of these fish species is distinct from that of higher vertebrates.
...
PMID:Molecular characterization of novel interferon gamma receptor 1 isoforms in zebrafish (Danio rerio) and goldfish (Carassius auratus L.). 1957 3

Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal and cancer cells, such as 5-bromo-2'-deoxyuridine (BrdU), distamycin A (DMA), aphidicolin and hydroxyurea, persistently activate Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and expression of interferon-stimulated genes (ISGs), such as MX1, OAS, ISG15, STAT1, PML, IRF1 and IRF7, in several human cancer cell lines. JAK1/STAT-activating ligands, interleukin 10 (IL10), IL20, IL24, interferon gamma (IFNgamma), IFNbeta and IL6, were also expressed by senescent cells, supporting autocrine/paracrine activation of JAK1/STAT. Furthermore, cytokine genes, including proinflammatory IL1, tumor necrosis factor and transforming growth factor families, were highly expressed. The strongest inducer of JAK/STAT signaling, cytokine production and senescence was BrdU combined with DMA. RNA interference-mediated knockdown of JAK1 abolished expression of ISGs, but not DNA damage signaling or senescence. Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNbeta-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence. These results highlight shared and unique features of drug-induced cellular senescence, and implicate induction of cancer secretory phenotype in chemotherapy.
...
PMID:Cytokine expression and signaling in drug-induced cellular senescence. 1980 7


<< Previous 1 2 3 4 5 6 Next >>

---