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

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

Cannabinoids, the active components of marijuana and their endogenous counterparts were reported as useful analgetic agents to accompany primary cancer treatment by preventing nausea, vomiting, and pain and by stimulating appetite. Moreover, they have been shown to inhibit cell growth and to induce apoptosis in tumor cells. Here, we demonstrate that anandamide, Delta(9)-tetrahydrocannabinol (THC), HU-210, and Win55,212-2 promote mitogenic kinase signaling in cancer cells. Treatment of the glioblastoma cell line U373-MG and the lung carcinoma cell line NCI-H292 with nanomolar concentrations of THC led to accelerated cell proliferation that was completely dependent on metalloprotease and epidermal growth factor receptor (EGFR) activity. EGFR signal transactivation was identified as the mechanistic link between cannabinoid receptors and the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 as well as prosurvival protein kinase B (Akt/PKB) signaling. Depending on the cellular context, signal cross-communication was mediated by shedding of proAmphiregulin (proAR) and/or proHeparin-binding epidermal growth factor-like growth factor (proHB-EGF) by tumor necrosis factor alpha converting enzyme (TACE/ADAM17). Taken together, our data show that concentrations of THC comparable with those detected in the serum of patients after THC administration accelerate proliferation of cancer cells instead of apoptosis and thereby contribute to cancer progression in patients.
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PMID:Cannabinoids induce cancer cell proliferation via tumor necrosis factor alpha-converting enzyme (TACE/ADAM17)-mediated transactivation of the epidermal growth factor receptor. 1502 28

Elevations in matrix metalloproteinase 1 (MMP-1) and MMP-3 have been found in patients with Lyme arthritis and in in vitro models of Lyme arthritis using cartilage explants and chondrocytes. The pathways by which B. burgdorferi, the causative agent of Lyme disease, induces the production of MMP-1 and MMP-3 have not been elucidated. We examined the role of the extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways in MMP induction by B. burgdorferi. Infection with B. burgdorferi results in rapid phosphorylation of p38 and JNK within 15 to 30 min. Inhibition of JNK and p38 MAPK significantly reduced B. burgdorferi-induced MMP-1 and MMP-3 expression. Inhibition of ERK1/2 completely inhibited the expression of MMP-3 in human chondrocytes following B. burgdorferi infection but had little effect on the expression of MMP-1. B. burgdorferi infection also induced phosphorylation and nuclear translocation of STAT-3 and STAT-6 in primary human chondrocytes. Expression of MMP-1 and MMP-3 was significantly inhibited by inhibition of JAK3 activity. Induction of MMP-1 and -3 following MAPK and JAK/STAT activation was cycloheximide sensitive, suggesting synthesis of intermediary proteins is required. Inhibition of tumor necrosis factor alpha (TNF-alpha) significantly reduced MMP-1 but not MMP-3 expression from B. burgdorferi-infected cells; inhibition of interleukin-1beta (IL-1beta) had no effect. Treatment of B. burgdorferi-infected cells with JAK and MAPK inhibitors significantly inhibited TNF-alpha induction, consistent with at least a partial role for TNF-alpha in B. burgdorferi-induced MMP-1 expression in chondrocytes.
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PMID:Borrelia burgdorferi-induced expression of matrix metalloproteinases from human chondrocytes requires mitogen-activated protein kinase and Janus kinase/signal transducer and activator of transcription signaling pathways. 1510 98

Two samples of diesel exhaust particles (DEPs) predominate in health effects research: an automobile-derived DEP (A-DEP) sample and the National Institute of Standards Technology standard reference material (SRM 2975) generated from a forklift engine. A-DEPs have been tested extensively for their effects on pulmonary inflammation and exacerbation of allergic asthmalike responses. In contrast, SRM 2975 has been tested thoroughly for its genotoxicity. In the present study, we combined physical and chemical analyses of both DEP samples with pulmonary toxicity testing in CD-1 mice to compare the two materials and to make associations between their physicochemical properties and their biologic effects. A-DEPs had more than 10 times the amount of extractable organic material and less than one-sixth the amount of elemental carbon compared with SRM 2975. Aspiration of 100 micro g of either DEP sample in saline produced mild acute lung injury; however, A-DEPs induced macrophage influx and activation, whereas SRM 2975 enhanced polymorphonuclear cell inflammation. A-DEPs stimulated an increase in interleukin-6 (IL-6), tumor necrosis factor alpha, macrophage inhibitory protein-2, and the TH2 cytokine IL-5, whereas SRM 2975 only induced significant levels of IL-6. Fractionated organic extracts of the same quantity of DEPs (100 micro g) did not have a discernable effect on lung responses and will require further study. The disparate results obtained highlight the need for chemical, physical, and source characterization of particle samples under investigation. Multidisciplinary toxicity testing of diesel emissions derived from a variety of generation and collection conditions is required to meaningfully assess the health hazards associated with exposures to DEPs. Key words: automobile, diesel exhaust particles, forklift, mice, pulmonary toxicity, SRM 2975.
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PMID:Sample characterization of automobile and forklift diesel exhaust particles and comparative pulmonary toxicity in mice. 1517 67

Sepsis caused by gram-positive bacteria lacking lipopolysaccharide (LPS) has become a major and increasing cause of mortality in intensive-care units. We have recently demonstrated that the gram-positive-specific bacterial cell wall component lipoteichoic acid (LTA) stimulates the release of the proinflammatory cytokines in Kupffer cells in culture. In the present study, we have started to assess the signal transduction events by which LTA induces the production of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and the anti-inflammatory cytokine IL-10 in rat Kupffer cells. LTA was found to trigger phosphorylation of mitogen-activated protein kinases (MAPK) (p38 MAPK and ERK 1/2) and protein kinase B (PKB). Compared to LPS, LTA was more potent in inducing PKB phosphorylation after 40 min, although we found that the cytokine responses were similar. For both bacterial molecules, blocking phosphatidylinositol 3-kinase (PI3-K; Ly294002) or Janus kinase 2 (JAK-2; AG490) particularly affected the induction of IL-6 and IL-10 release, whereas TNF-alpha levels were strongly reduced by inhibition of Src family tyrosine kinases (PP2). All three cytokines were reduced by inhibition of p38 MAPK (SB202190) or the broad-range tyrosine kinase inhibitor genistein, whereas IL-6 release was particularly blocked by inhibition of ERK 1/2 (PD98059). Divergences in the regulatory pathways controlling TNF-alpha, IL-10, and IL-6 production in Kupffer cells following LPS or LTA stimulation may create a basis for understanding how the balance between pro- and anti-inflammatory cytokines is regulated in the liver following infections by gram-positive or gram-negative bacteria.
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PMID:The phosphatidylinositol 3-kinase/protein kinase B signaling pathway is activated by lipoteichoic acid and plays a role in Kupffer cell production of interleukin-6 (IL-6) and IL-10. 1538 69

Forkhead transcription factors of the FOXO class are negatively regulated by PKB/c-Akt in response to insulin/IGF signalling, and are involved in regulating cell cycle progression and cell death. Here we show that, in contrast to insulin signalling, low levels of oxidative stress generated by treatment with H2O2 induce the activation of FOXO4. Upon treatment of cells with H2O2, the small GTPase Ral is activated and this results in a JNK-dependent phosphorylation of FOXO4 on threonine 447 and threonine 451. This Ral-mediated, JNK-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of FOXO4 after H2O2 treatment. In addition, we show that this signalling pathway is also employed by tumor necrosis factor alpha to activate FOXO4 transcriptional activity. FOXO members have been implicated in cellular protection against oxidative stress via the transcriptional regulation of manganese superoxide dismutase and catalase gene expression. The results reported here, therefore, outline a homeostasis mechanism for sustaining cellular reactive oxygen species that is controlled by signalling pathways that can convey both negative (PI-3K/PKB) and positive (Ras/Ral) inputs.
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PMID:FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. 1553 82

We previously reported that tumor necrosis factor alpha receptor- and Fas-associated FLASH interacts with one of the p160 nuclear receptor coactivators, glucocorticoid receptor-interacting protein (GRIP) 1, at its nuclear receptor-binding (NRB) domain, and that inhibits the transcriptional activity of the glucocorticoid receptor (GR) by interfering with association of GR and GRIP1. Here, we further examined the specificity of FLASH suppressive effect and the physical/functional interactions between this protein and two other p160 family subtypes. The suppressive effect of FLASH on GR transactivation was observed in several cell lines and on the chromatin-integrated mouse mammary tumor virus (MMTV) promoter. FLASH strongly interacted with the NRB domain of the thyroid hormone receptor activator molecule (TRAM) 1, a member of the steroid hormone receptor coactivator (SRC) 3/nuclear receptor coactivator (N-CoA) 3 subtypes, as well as with SRC2/N-CoA2 p160 coactivator GRIP1, while its interaction with SRC1a, one of the SRC1/N-CoA1 proteins, was faint in yeast two-hybrid assays. Accordingly, FLASH strongly suppressed TRAM1- and GRIP1-induced enhancement of GR-stimulated transactivation of the MMTV promoter in HCT116 cells, while it did not affect SRC1a-induced potentiation of transcription. Furthermore, FLASH suppressed androgen- and progesterone receptor-induced transcriptional activity, but did not influence estrogen receptor-induced transactivation, possibly due to their preferential use of p160 coactivators in HCT116 and HeLa cells. Thus, FLASH differentially suppresses steroid hormone receptor-induced transcriptional activity by interfering with their association with SRC2/N-CoA2 and SRC3/N-CoA3 but not with SRC1/N-CoA1.
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PMID:FLASH interacts with p160 coactivator subtypes and differentially suppresses transcriptional activity of steroid hormone receptors. 1569 40

Using flow cytometry, we observed that interleukin-18 (IL-18) primed human neutrophils (PMNs) in whole blood to produce superoxide anion (O2 degrees-) in response to N-formyl peptide (fMLP) stimulation, whereas IL-18 alone had no significant effect. In contrast to tumor necrosis factor alpha (TNF-alpha), which is a cytokine known to strongly prime O2 degrees- production, IL-18 did not induce either p47phox phosphorylation or its translocation from the cytosol to the plasma membrane. However, IL-18 increased PMN degranulation, as shown by increased levels of cytochrome b558 and CD11b expression at the PMN surface. Moreover, addition of IL-18 to whole blood for 45 min reduced the ability of PMNs to bind to fMLP, suggesting endocytosis of fMLP receptors, as visualized by confocal microscopy. 2,3-Butanedione 2-monoxime, which inhibits endosomal recycling of plasma membrane components back to the cell surface, concomitantly accentuated the diminution of fMLP binding at the PMN surface and increased IL-18 priming of O2 degrees- production by PMNs in response to fMLP. This suggests that fMLP receptor endocytosis could account, at least in part, for the priming of O2 degrees- production. In addition, genistein, a tyrosine kinase inhibitor, and SB203580, a p38 mitogen-activated protein kinase (p38MAPK) inhibitor, completely reversed the decreased level of fMLP binding and increased the level of CD11b expression after IL-18 treatment. Flow cytometric analysis of intact PMNs in whole blood showed that IL-18 increased p38MAPK phosphorylation and tyrosine phosphorylation. In particular, IL-18 induced phosphorylation of focal adhesion kinase (p125FAK), which has been implicated in cytoskeleton reorganization. Taken together, our findings suggest several mechanisms that are likely to regulate cytokine-induced priming of the oxidative burst in PMNs in their blood environment.
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PMID:Interleukin-18 primes the oxidative burst of neutrophils in response to formyl-peptides: role of cytochrome b558 translocation and N-formyl peptide receptor endocytosis. 1575 57

Human beta-defensins are antimicrobial peptides produced by epithelial cells. To date, 28 beta-defensins have been described and the expression of a select few has been classified as constitutive or inducible. Most studies have evaluated expression and regulation using a limited number of primary cell cultures or immortalized cell lines. The goal of this study was to quantitatively assess the in vitro expression and inducibility profiles of human beta-defensins, HBD-1, HBD-2, and HBD-3 across a number of primary gingival keratinocyte cultures. Cultured cells from 14 human subjects were stimulated with interleukin-1 beta (IL-1beta), IL-2, IL-6, IL-8, IL-12, tumor necrosis factor alpha (TNF-alpha), gamma interferon (IFN-gamma) or Escherichia coli lipopolysaccharide (LPS) and analyzed by reverse transcription (RT)-PCR. A subset of cultures were quantitatively assessed by real-time PCR. HBD-1 presented the highest and most heterogeneous expression at the basal level (non-stimulated) as compared to expression of HBD-2 and HBD-3, which was significantly lower and homogeneous. IFN-gamma was a primary inducer for HBD-1 and HBD-3, while IL-1beta and TNF-alpha were primary inducers for HBD-2. Sporadic induction was seen for IL-2, IL-6 and LPS. Synergistic expression was seen when various cytokines were combined. Interestingly, the induction potential of each beta-defensin was directly correlated to its basal expression. An inhibitor of JAK2 kinase (Janus kinase), down-regulated IFN-gamma-induced HBD-1 and HBD-3 expression, suggesting a role for the JAK/signal transducer and activator of transcription (STAT) signaling pathway in their expression. HBD-2 protein expression of supernatants and cell lysates paralleled mRNA expression. The results suggest that beta-defensin expression and induction in gingival keratinocytes is similar to that seen in other tissue. However, the novel finding of considerable variation among induction levels and the correlation of the induction with basal expression suggests that these innate response elements may play a key role in susceptibility or resistance to disease in the oral cavity.
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PMID:Correlation between beta-defensin expression and induction profiles in gingival keratinocytes. 1582 97

Signal regulatory protein alpha (SIRPalpha) is a glycoprotein receptor that recruits and signals via the tyrosine phosphatases SHP-1 and SHP-2. In macrophages SIRPalpha can negatively regulate the phagocytosis of host cells and the production of tumor necrosis factor alpha. Here we provide evidence that SIRPalpha can also stimulate macrophage activities, in particular the production of nitric oxide (NO) and reactive oxygen species. Ligation of SIRPalpha by antibodies or soluble CD47 triggers inducible nitric oxide synthase expression and production of NO. This was not caused by blocking negative-regulatory SIRPalpha-CD47 interactions. SIRPalpha-induced NO production was prevented by inhibition of the tyrosine kinase JAK2. JAK2 was found to associate with SIRPalpha in macrophages, particularly after SIRPalpha ligation, and SIRPalpha stimulation resulted in JAK2 and STAT1 tyrosine phosphorylation. Furthermore, SIRPalpha-induced NO production required the generation of hydrogen peroxide (H(2)O(2)) by a NADPH oxidase (NOX) and the phosphatidylinositol 3-kinase (PI3-K)-dependent activation of Rac1, an intrinsic NOX component. Finally, SIRPalpha ligation promoted SHP-1 and SHP-2 recruitment, which was both JAK2 and PI3-K dependent. These findings demonstrate that SIRPalpha ligation induces macrophage NO production through the cooperative action of JAK/STAT and PI3-K/Rac1/NOX/H(2)O(2) signaling pathways. Therefore, we propose that SIRPalpha is able to function as an activating receptor.
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PMID:Signal regulatory protein alpha ligation induces macrophage nitric oxide production through JAK/STAT- and phosphatidylinositol 3-kinase/Rac1/NAPDH oxidase/H2O2-dependent pathways. 1605 27

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.
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PMID:Macrophage-targeted photodynamic therapy: scavenger receptor expression and activation state. 1616 23


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