Matches in Nanopublications for { ?s <http://www.w3.org/ns/prov#value> ?o ?g. }
- _3 value "Understanding the response of innate immune cells to pathogens may provide insights to host defenses and the tactics used by pathogens to circumvent these defenses. We used DNA microarrays to explore the responses of human macrophages to a variety of bacteria. Macrophages responded to a broad range of bacteria with a robust, shared pattern of gene expression. The shared response includes genes encoding receptors, signal transduction molecules, and transcription factors. This shared activation program transforms the macrophage into a cell primed to interact with its environment and to mount an immune response. Further study revealed that the activation program is induced by bacterial components that are Toll-like receptor agonists, including lipopolysaccharide, lipoteichoic acid, muramyl dipeptide, and heat shock proteins. Pathogen-specific responses were also apparent in the macrophage expression profiles. Analysis of Mycobacterium tuberculosis-specific responses revealed inhibition of interleukin-12 production, suggesting one means by which this organism survives host defenses. These results improve our understanding of macrophage defenses, provide insights into mechanisms of pathogenesis, and suggest targets for therapeutic intervention." provenance.
- _3 value "Understanding the response of innate immune cells to pathogens may provide insights to host defenses and the tactics used by pathogens to circumvent these defenses. We used DNA microarrays to explore the responses of human macrophages to a variety of bacteria. Macrophages responded to a broad range of bacteria with a robust, shared pattern of gene expression. The shared response includes genes encoding receptors, signal transduction molecules, and transcription factors. This shared activation program transforms the macrophage into a cell primed to interact with its environment and to mount an immune response. Further study revealed that the activation program is induced by bacterial components that are Toll-like receptor agonists, including lipopolysaccharide, lipoteichoic acid, muramyl dipeptide, and heat shock proteins. Pathogen-specific responses were also apparent in the macrophage expression profiles. Analysis of Mycobacterium tuberculosis-specific responses revealed inhibition of interleukin-12 production, suggesting one means by which this organism survives host defenses. These results improve our understanding of macrophage defenses, provide insights into mechanisms of pathogenesis, and suggest targets for therapeutic intervention." provenance.
- _4 value "This study showed that various forms of cell stress, such as chemical stress (sodium arsenite), osmotic stress, or heat shock lead to substantial formation of 5-LO products in freshly isolated human polymorphonuclear leukocytes" provenance.
- _4 value "This study showed that various forms of cell stress, such as chemical stress (sodium arsenite), osmotic stress, or heat shock lead to substantial formation of 5-LO products in freshly isolated human polymorphonuclear leukocytes" provenance.
- _4 value "Reduction in the expression of the intermediate filament protein nestin in the medial aspect of the notch1 mutant cerebellar primordium was observed when compared with control wildtype littermates." provenance.
- _5 value "Acute and chronic treatments of mice with the glutathione-depleting agent, L-buthionine-(SR)-sulfoximine (BSO), impaired the mineralocorticoid receptor (MR)-dependent biological response by inhibiting aldosterone binding" provenance.
- _7 value "# Ariadne: Dermo-1 interacted directly with MEF2 and selectively repressed the MEF2 transactivation domain. [Regulation]" provenance.
- _5 value "The counterregulation of catecholamine action by insulin includes insulin-stimulated sequestration of the beta(2)-adrenergic receptor" provenance.
- _4 value "The increase in beta-catenin protein preceded that of conductin by about 1 to 2 hour, the peak of beta-catenin was detected between 2 and 6 hours, while that of conductin was seen between 4 and 8 hours following exposure of cells to wnt-1." provenance.
- _5 value "Electrophoretic mobility shift assays revealed that treatment of hepatoma cells or cultured rat hepatocytes with 1 mM 8-Br-cAMP or glucagon reduced binding of FP330-3' by HNF4 by half. In vitro phosphorylation of HNF4 by PKA decreased binding to FP330-3'" provenance.
- _5 value "Electrophoretic mobility shift assays revealed that treatment of hepatoma cells or cultured rat hepatocytes with 1 mM 8-Br-cAMP or glucagon reduced binding of FP330-3' by HNF4 by half. In vitro phosphorylation of HNF4 by PKA decreased binding to FP330-3'" provenance.
- _6 value "After activating Ras using EGF, the GTP-bound form of Ras was precipitated with GST-RBD (GST-Raf containing Ras binding domain). Precipitated Ras was detected using the HA-antibody. As shown in Fig. 5D, in the presence of EGF, the amount of GTP-bound Ras increased over that of the control. Levels of the GTP-bound Ras significantly decreased in cells expressing DIP1/2; however, DIP1/2m failed to stimulate Ras GTPase in cells treated with EGF." provenance.
- _6 value "After activating Ras using EGF, the GTP-bound form of Ras was precipitated with GST-RBD (GST-Raf containing Ras binding domain). Precipitated Ras was detected using the HA-antibody. As shown in Fig. 5D, in the presence of EGF, the amount of GTP-bound Ras increased over that of the control. Levels of the GTP-bound Ras significantly decreased in cells expressing DIP1/2; however, DIP1/2m failed to stimulate Ras GTPase in cells treated with EGF." provenance.
- _6 value "After activating Ras using EGF, the GTP-bound form of Ras was precipitated with GST-RBD (GST-Raf containing Ras binding domain). Precipitated Ras was detected using the HA-antibody. As shown in Fig. 5D, in the presence of EGF, the amount of GTP-bound Ras increased over that of the control. Levels of the GTP-bound Ras significantly decreased in cells expressing DIP1/2; however, DIP1/2m failed to stimulate Ras GTPase in cells treated with EGF." provenance.
- _6 value "After activating Ras using EGF, the GTP-bound form of Ras was precipitated with GST-RBD (GST-Raf containing Ras binding domain). Precipitated Ras was detected using the HA-antibody. As shown in Fig. 5D, in the presence of EGF, the amount of GTP-bound Ras increased over that of the control. Levels of the GTP-bound Ras significantly decreased in cells expressing DIP1/2; however, DIP1/2m failed to stimulate Ras GTPase in cells treated with EGF." provenance.
- _6 value "After activating Ras using EGF, the GTP-bound form of Ras was precipitated with GST-RBD (GST-Raf containing Ras binding domain). Precipitated Ras was detected using the HA-antibody. As shown in Fig. 5D, in the presence of EGF, the amount of GTP-bound Ras increased over that of the control. Levels of the GTP-bound Ras significantly decreased in cells expressing DIP1/2; however, DIP1/2m failed to stimulate Ras GTPase in cells treated with EGF." provenance.
- _6 value "After activating Ras using EGF, the GTP-bound form of Ras was precipitated with GST-RBD (GST-Raf containing Ras binding domain). Precipitated Ras was detected using the HA-antibody. As shown in Fig. 5D, in the presence of EGF, the amount of GTP-bound Ras increased over that of the control. Levels of the GTP-bound Ras significantly decreased in cells expressing DIP1/2; however, DIP1/2m failed to stimulate Ras GTPase in cells treated with EGF." provenance.
- _3 value "These results strongly suggest that STAT3 in keratinocytes plays a critical role in turnover of tyrosine phosphorylation of p130(cas), modulating cell adhesiveness to the substratum leading to growth factor-dependent cell migration." provenance.
- _3 value "Resveratrol at 10(-5) M inhibited the expression of the autocrine growth stimulators transforming growth factor-alpha (TGF-alpha), PC cell-derived growth factor, and insulin-like growth factor I receptor mRNA." provenance.
- _6 value "These findings suggest that the NPY Y(1) receptor induces the expression of CRE containing target genes through the CaM kinase-CREB pathway, and inhibits CRE containing genes when cellular cAMP levels are elevated." provenance.
- _4 value "However, in Bim-/- mice, the percentage of apoptotic cells observed after LY294002 (PI3K inhibitor) treatment was significantly reduced compared with wild-type. (Annexin V staining)" provenance.
- _4 value "A 41% and 27% decrease in catalase activity was detected in cells treated with GH, whereas IGF-1 reduced CAT activity levels to a greater extent than GH (P < 0.0001). The activity and protein levels of GPX were also significantly depressed in cells treated with GH, whereas activity alone was decreased in cells treated with IGF-1 (P < 0.04). GH significantly suppressed MnSOD levels by 40% and 66% in 1.0 and 0.1 microg/ml concentrations, respectively. Similarly, IGF-1 decreased MnSOD protein levels" provenance.
- _5 value "A 41% and 27% decrease in catalase activity was detected in cells treated with GH, whereas IGF-1 reduced CAT activity levels to a greater extent than GH (P < 0.0001). The activity and protein levels of GPX were also significantly depressed in cells treated with GH, whereas activity alone was decreased in cells treated with IGF-1 (P < 0.04). GH significantly suppressed MnSOD levels by 40% and 66% in 1.0 and 0.1 microg/ml concentrations, respectively. Similarly, IGF-1 decreased MnSOD protein levels" provenance.
- _4 value "he expression of pulmonary CYP2E1 mRNA and protein have been established in several studies 17, 19, 21, 29, 37, 42, 43. CYP2E1 is an interesting CYP form because it is the most active CYP enzyme in forming oxygen radicals, causing tissue injury 44" provenance.
- _4 value "tryosine phosphorylation of gp130 was observed in fibroblasts after stimulation with all the cytokines" provenance.
- _4 value "tryosine phosphorylation of gp130 was observed in fibroblasts after stimulation with all the cytokines" provenance.
- _7 value "NF1/X physically and specifically interacts with Sp1 via its subtype-specific domain and blocks Sp1 induction of the promoter." provenance.
- _5 value "NF1/X repressed PDGF-A promoter-dependent transcription and endogenous mRNA expression," provenance.
- _7 value "We report that inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-1/2 blocked BCR-induced activation of extracellular signal-regulated kinase (ERK)." provenance.
- _4 value "In contrast to previously recognized NFATc kinases, wild-type Pim-1 enhances NFATc-dependent transactivation and IL-2 production in Jurkat T cells, while kinase-deficient Pim-1 mutants inhibit them in a dominant negative fashion." provenance.
- _5 value "IL-4 induces p38 MAPK activation in human dermal fibroblasts Since inhibition of p38 MAPK significantly decreased IL-4-induced TIMP-2 expression, we determined the activation of p38 MAPK by immunoblotting using Abs specific for phosphorylated, activated forms of p38 MAPK (Thr 180 /Tyr 182 )." provenance.
- _3 value "This binding was enhanced in a time-dependent manner by pre-exposure of RAEC to LPS, IL-6, or TNF-alpha, the increased binding of C5a being associated with increased levels of mRNA for the C5a receptor (C5aR)." provenance.
- _4 value "Stroke is one of the leading causes of death in major industrial countries. Many factors contribute to the cellular damage resulting from ischemia/reperfusion (I/R). Experimental data indicate an important role for oxidative stress and the inflammatory cascade during I/R. We are testing the hypothesis that the mechanism of protection against I/R damage observed in transgenic mice overexpressing human antioxidant enzymes (particularly intracellular glutathione peroxidase) involves the modulation of inflammatory response as well as reduced sensitivity of neurons to cytotoxic cytokines. Transgenic animals show significant reduction of expression of chemokines, IL-6, and cell death-inducing ligands as well as corresponding receptors in a focal cerebral I/R model. Reduction of DNA binding activity of consensus and potential AP-1 binding sites in mouse Fas ligand promoter sequence was observed in nuclear extracts from transgenic mice overexpressing intracellular glutathione peroxidase compared with normal animals following I/R. This effect was accompanied by modulation of the c-Jun N-terminal kinase/stress-activated protein kinase pathway. Cultured primary neurons from the transgenic mice demonstrated protection against hypoxia/reoxygenation injury as well as cytotoxicity after TNF-alpha and Fas ligand treatment. These results indicate that glutathione peroxidase-sensitive reactive oxygen species play an important role in regulation of cell death during cerebral I/R by modulating intrinsic neuronal sensitivity as well as brain inflammatory reactions." provenance.
- _4 value "MBP stimulated splenocytes from C-GSF treated mice showed an increase in the expression of IL4 as compared with the excipient treated mice." provenance.
- _4 value "Treatment with G-CSF prevented the mRNA expression of IL2 in EAE induced mice." provenance.
- _5 value "The HB-EGF precursor within this complex is processed by MMP-7, and the resulting mature HB-EGF engages and activates its receptor, ErbB4, leading to, among other events, cell survival." provenance.
- _5 value "Modified assertion" provenance.
- _5 value "A substantial body of literature indicates that endothelial COX-2 activity is upregulated by a number of cytokines and mitogenic stimuli, including Interleukin-1 alpha and beta (IL-l alpha and beta), tumour necrosis factor alpha (TNFa), transforming growth factor beta (TGFbeta), phorbol ester, lipolysaccharide (LPS) and interferon gamma (IFNy) I2 13." provenance.
- _5 value "A substantial body of literature indicates that endothelial COX-2 activity is upregulated by a number of cytokines and mitogenic stimuli, including Interleukin-1 alpha and beta (IL-l alpha and beta), tumour necrosis factor alpha (TNFa), transforming growth factor beta (TGFbeta), phorbol ester, lipolysaccharide (LPS) and interferon gamma (IFNy) I2 13." provenance.
- _5 value "A substantial body of literature indicates that endothelial COX-2 activity is upregulated by a number of cytokines and mitogenic stimuli, including Interleukin-1 alpha and beta (IL-l alpha and beta), tumour necrosis factor alpha (TNFa), transforming growth factor beta (TGFbeta), phorbol ester, lipolysaccharide (LPS) and interferon gamma (IFNy) I2 13." provenance.
- _4 value "IL-6 and KC, the latter of which is a murine CXC homologue of human GRO, are two endogenously expressed LPS- and IL-1b-inducible gene products, the expression of which is dependent upon NF-kB activation (25, 26). Similar to luciferase activity, IL-6 production (Figure 2c) and KC production (Figure 2d) were both enhanced in FADD-/- MEFs compared with FADD+/+ MEFs following LPS or IL-1b exposure. Together, these data demonstrate that NF-kB-dependent gene expression is enhanced in the absence of FADD. " provenance.
- _4 value "IL-6 and KC, the latter of which is a murine CXC homologue of human GRO, are two endogenously expressed LPS- and IL-1b-inducible gene products, the expression of which is dependent upon NF-kB activation (25, 26). Similar to luciferase activity, IL-6 production (Figure 2c) and KC production (Figure 2d) were both enhanced in FADD-/- MEFs compared with FADD+/+ MEFs following LPS or IL-1b exposure. Together, these data demonstrate that NF-kB-dependent gene expression is enhanced in the absence of FADD. " provenance.
- _5 value "Table1: Down-regulation by progesterone (fold) Gene PRA PRB Fibronectin None 2.8 Integrin a3 None 2.8 Integrin B1 None >10 Integrin B3 8 5.6 Cadherin 6 6 8 Differences between the PR isoforms were evident: in general, PRB had a greater inhibitory effect on cellular adhesion molecule expression compared with PRA. Only PRB significantly inhibited the expression of fibronectin and the integrins 3 and B1, but both PR isoforms inhibited cadherin 6 and integrin B3." provenance.
- _5 value "Table1: Down-regulation by progesterone (fold) Gene PRA PRB Fibronectin None 2.8 Integrin a3 None 2.8 Integrin B1 None >10 Integrin B3 8 5.6 Cadherin 6 6 8 Differences between the PR isoforms were evident: in general, PRB had a greater inhibitory effect on cellular adhesion molecule expression compared with PRA. Only PRB significantly inhibited the expression of fibronectin and the integrins 3 and B1, but both PR isoforms inhibited cadherin 6 and integrin B3." provenance.
- _5 value "Table1: Down-regulation by progesterone (fold) Gene PRA PRB Fibronectin None 2.8 Integrin a3 None 2.8 Integrin B1 None >10 Integrin B3 8 5.6 Cadherin 6 6 8 Differences between the PR isoforms were evident: in general, PRB had a greater inhibitory effect on cellular adhesion molecule expression compared with PRA. Only PRB significantly inhibited the expression of fibronectin and the integrins 3 and B1, but both PR isoforms inhibited cadherin 6 and integrin B3." provenance.
- _4 value "Site-directed mutagenesis studies demonstrate that three of the four NF-kappaB elements in the CD40 promoter are required for IFN-gamma-induced CD40 promoter activity." provenance.
- _3 value "ADAM1, 8, 10, 12, 15, 17, 20, and 21 mRNAs are expressed in blood monocytes incubated with control antibody, anti-FRP-1/CD98 antibody, or RANKL + M-CSF, while ADAM2, 7, 11, 13, 19, 23, 29, and 30 mRNAs could not be detected in these blood monocytes." provenance.
- _3 value "ADAM1, 8, 10, 12, 15, 17, 20, and 21 mRNAs are expressed in blood monocytes incubated with control antibody, anti-FRP-1/CD98 antibody, or RANKL + M-CSF, while ADAM2, 7, 11, 13, 19, 23, 29, and 30 mRNAs could not be detected in these blood monocytes." provenance.
- _4 value "AVP acts as a potent growth factor, inducing DNA synthesis and cell proliferation through ERK, Ca, PKC, EGFR tyrosine kinase and Src dependent pathways" provenance.
- _5 value "Phosphorylation of PDE3A and activation of PDE3A and PDE4 were blocked by the PKA inhibitors [protein kinase inhibitor (PKI) and H-89]" provenance.
- _6 value "Phosphorylation of PDE3A and activation of PDE3A and PDE4 were blocked by the PKA inhibitors [protein kinase inhibitor (PKI) and H-89]" provenance.
- _3 value "Sodium nitroprusside inhibited PDE3 activity and augmented forskolin- and isoproterenol-stimulated cAMP levels; PDE3 inhibition was reversed by blockade of cGMP synthesis." provenance.
- _5 value "The results indicate that PKA regulates cAMP levels in smooth muscle via stimulatory phosphorylation of PDE3A and PDE4 and inhibitory phosphorylation of adenylyl cyclase type V/VI. Concurrent generation of cGMP inhibits PDE3 activity and augments cAMP levels." provenance.
- _4 value "The results indicate that PKA regulates cAMP levels in smooth muscle via stimulatory phosphorylation of PDE3A and PDE4 and inhibitory phosphorylation of adenylyl cyclase type V/VI. Concurrent generation of cGMP inhibits PDE3 activity and augments cAMP levels." provenance.
- _6 value "The results indicate that PKA regulates cAMP levels in smooth muscle via stimulatory phosphorylation of PDE3A and PDE4 and inhibitory phosphorylation of adenylyl cyclase type V/VI. Concurrent generation of cGMP inhibits PDE3 activity and augments cAMP levels." provenance.
- _4 value "MCF7-Fas cells expressing XAIP showed the significant inhibition of Caspase-2 and CRADD mediated apoptosis ." provenance.
- _4 value "Furthermore, mouse PLAGL2 and Zac1 can activate the transcription of the LDHA promoter, which contains HRE ( 17 )." provenance.
- _5 value "Furthermore, the transient expression of PLAGL2 led to the stimulation of luciferase reporter activities of the LDHA and erythropoietin promoters that carry HRE ( 17 )." provenance.
- _3 value "Genes induced by retinoic acid" provenance.
- _3 value "Genes induced by retinoic acid" provenance.
- _4 value "Here we demonstrate that insulin induces an increase in the plasma membrane abundance of SAT2 in a phosphatidylinositol 3-kinase-dependent manner" provenance.
- _6 value "In vitro, Abeta(1-42) interacts with ACT The mixture of soluble Abeta and an ACT/Abeta complex formed by 2 hr incubation at a 10:1 molar ratio of Abeta:ACT strongly induce cellular proliferation and expression of transcription factors peroxisome proliferator-activated receptor-gamma (PPARgamma) and NFkappaB, and also increase uptake and depress degradation of native and oxidised low-density lipoprotein (LDL) by cells." provenance.
- _5 value "In vitro, Abeta(1-42) interacts with ACT The mixture of soluble Abeta and an ACT/Abeta complex formed by 2 hr incubation at a 10:1 molar ratio of Abeta:ACT strongly induce cellular proliferation and expression of transcription factors peroxisome proliferator-activated receptor-gamma (PPARgamma) and NFkappaB, and also increase uptake and depress degradation of native and oxidised low-density lipoprotein (LDL) by cells." provenance.
- _3 value "ERdj4 mRNA expression was detected in all human tissues examined but showed the highest level of the expression in the liver, kidney, and placenta. We found that ERdj4 was highly induced at both the mRNA and protein level in response to ER stress" provenance.
- _3 value "A comparison of genes transcriptionally up-regulated in senescence to those in which expression is significantly down-regulated in immortalized HPECs identified three genes: the chemokine BRAK, DOC1, and a member of the insulin-like growth factor axis, IGFBP-3. Expression of these genes is found to be uniformly lost in human prostate cancer cell lines and xenografts, and previously, their inactivation was documented in tumor samples." provenance.
- _3 value "suggest that the leucine zipper structure in TSC-22 protein is an active domain that negatively regulates the growth of salivary gland cancer cells." provenance.
- _3 value "Cholestasis is associated with retention of potentially toxic bile acids and profound cytoskeletal alterations of hepatocytes. Given the well-established cytoprotective role of hepatocyte keratins this study aimed to determine the effects of cholestasis on the cytokeratin (CK) intermediate filament network in mouse liver. Mice were subjected to common bile duct ligation or sham operation. Mice were also fed a cholic acid or ursodeoxycholic acid (UDCA)-supplemented diet (0.1%, 0.5%, and 1%) or control diet for 7 days. CK 8 and CK 18 expression was studied by competitive reverse transcriptase-polymerase chain reaction, in situ hybridization, Western blot analysis, and immunofluorescence microscopy. Common bile duct ligation and cholic acid feeding significantly stimulated CK 8 and CK 18 mRNA and protein levels compared to controls, whereas UDCA had no effect. CK overexpression was accompanied by pronounced phosphorylation. Our results show that potentially toxic bile acids induce hepatocytic CK 8 and CK 18 expression and phosphorylation whereas nontoxic UDCA has no effect on CKs. Thus, increased hepatocellular CK expression and phosphorylation in cholestasis may be caused by retention of toxic bile acids and reflect a hepatocellular stress response with potential beneficial effects." provenance.
- _4 value "MCP-1 protein expression induced by IFN-gamma and CD40L (24 hours) was significantly decreased by the ERK1/2 MAPK pathway inhibitor, U0126. U0126 treatment at 10 micromol/L significantly reduced IFN- gamma and CD40L-induced MCP-1 protein production, bringing the levels of MCP-1 to baseline." provenance.
- _4 value "RANTES mRNA and protein expression was induced by CD40L and IFN-gamma. CD40L induced RANTES expression was potentiated by IFN-gamma." provenance.
- _4 value "Treatment of cells with IFN-gamma and CD40L induced the phosphorylation of ERK2 after 10 min of stimulation. Pretreatment with PD98059 (MAPK inhibitor) at 30 micro mol/L abrogated this induction." provenance.
- _4 value "Although this work confirms that PDE4 appears to be the most important PDE target for induction of apoptosis in CLL, combination therapy with PDE3 and PDE4 inhibitors or use of dual-selective drugs may be of benefit in a subset of relatively PDE4-inhibitor resistant CLL patients." provenance.
- _4 value "In conclusion, a functional complex of cis-elements within the proximal human ABCA1 promoter associated with the transcription factors Sp1/3, upstream stimulatory factors 1 and 2, and hepatic nuclear factor 1alpha has been characterized, which allows a subtle tissue-specific regulation of ABCA1 gene expression." provenance.
- _5 value "Modified assertion" provenance.
- _6 value " However, the functions of uPA are not limited to the proteolytic activation of plasmin and of the growth factors on the cell surface. Recently accumulated data suggest that binding of uPA to membrane receptors on certain cells also directly initiates signaling cascades involved in the regulation of cell migration and proliferation independently of the ability of uPA to activate the growth factors. Thus, uPA-induced cell migration is associated with the activation of Janus kinases and of nonreceptor Src-kinases in certain cells [47-49]." provenance.
- _6 value "Both uPA itself and uPA-generated plasmin can activate the latent matrix metalloproteinases and elastase [46, 148], which are responsible for the subsequent degradation of the extracellular matrix, during the endothelial cell migration and invasion. Moreover these two proteases activate virtually all growth factors involved in angiogenesis [42-45, 147, 149]. Hypoxia has been shown to increase the expression of angiogenic growth factors, but uPA and plasmin are required to provide proteolytic activation of the latent forms or release of matrix-bound growth factors." provenance.
- _2 value "Moreover, risk factors for the development of atherosclerosis, such as obesity, insulin-independent diabetes mellitus, hyperlipidemia, and arterial hypertension are found to correlate with an increased level of PAI-1 [102]." provenance.
- _5 value "The TGF-beta inhibits in vitro proliferation of endothelial cells inducing their apoptosis but stimulates in vivo angiogenesis [176]. TGF-beta also stimulates VEGF expression in fibroblasts, especially under conditions of hypoxia that often occurs in tumors or in tissue ischemia caused by disorders in the main blood flow [177]." provenance.
- _4 value "The involvement of urokinase in tissue morphogenesis is also due to its ability to stimulate the cell proliferation. A mitogenic effect of uPA has been shown for various cells; however, its mechanism remains unclear in detail and seems to vary depending on the cell type. It was originally conceived that uPA can affect mitogenesis by a direct proteolytic- or plasmin-mediated activation of latent growth factors, such as HGF, bFGF, and TGF-beta [42-45]." provenance.
- _3 value "The pro-angiogenic growth factors bFGF and VEGF induce in vitro migration of endothelial cells and up-regulate uPAR [155-157]." provenance.
- _3 value "The significance of this increased tPA expression remains unclear. As tPA has features of a mitogen for SMC [115], it is suggested that tPA expression should provide plaque growth. However, in tPA deficient transgenic mice with overexpression of apolipoprotein the lipid stripe development induced by a cholesterol-rich diet was the same as in the wild type animals [64]." provenance.
- _3 value "The two plasminogen activators are mainly different in the structural determinants located in the noncatalytic regions of the proteins that are responsible for the enzyme binding to various components of the cell surface and of the cell environment. Thus, in the noncatalytic N-terminal region of the tPA molecule there are two additional domains as compared to the uPA molecule: a finger-domain and the second kringle-domain, which are responsible for specific binding to fibrin [24]. Precise timing and location of adequate extracellular proteolysis is provided by multiple mechanisms among which the mechanisms regulating the expression of plasminogen activators and of their inhibitors are especially important. A wide spectrum of hormones, growth factors, and cell environment factors are involved in the regulation of expression of the genes of plasminogen activators and of their inhibitors. The expression of uPA is activated by various inflammatory factors: cytokines [25], growth factors [26], and tumor promotors, such as phorbol-12-myristate-13-acetate [27], whereas antiinflammatory agents, such as glucocorticoids, inhibit the expression of uPA [28]." provenance.
- _3 value "Under natural conditions, ischemia (hypoxia) and inflammation [146] are the major triggers of angiogenesis, and the angiogenic factors, especially VEGF, bFGF, HGF, TGF-beta, and PDGF inducing endothelial cell proliferation and migration, play the key role in the process [145-147]." provenance.
- _2 value "Urokinase receptor expression by endothelial cells localizing uPA on cell surface is an important moment in the initiation of angiogenesis. Hypoxia, which is important for the in vivo stimulation of angiogenesis, has been shown to induce both the expression VEGF receptors and of urokinase receptor in umbilical vein endothelial cell culture (HUVEC) [154, 155]." provenance.
- _3 value "Urokinase receptor expression by endothelial cells localizing uPA on cell surface is an important moment in the initiation of angiogenesis. Hypoxia, which is important for the in vivo stimulation of angiogenesis, has been shown to induce both the expression VEGF receptors and of urokinase receptor in umbilical vein endothelial cell culture (HUVEC) [154, 155]." provenance.
- _4 value "This activity resides in the C terminus of the enzyme, which, by itself, promotes microtubule assembly at higher mole ratios. Phosphorylation of CNP interferes with its assembly-promoting activity, as does deletion of the C terminus, which leads to abnormal microtubule distribution in the cell. " provenance.
- _4 value "Modified assertion" provenance.
- _3 value "PTX, like exogenous db-cAMP, inhibited in a dose-dependent manner the basal and TNF-alpha-modulated IEC18 cell proliferation; this effect was partly prevented by PKI." provenance.
- _4 value "PTX, like exogenous db-cAMP, inhibited in a dose-dependent manner the basal and TNF-alpha-modulated IEC18 cell proliferation; this effect was partly prevented by PKI." provenance.
- _3 value "The drop in TGF-alpha mRNA is related to increasing intracellular cAMP" provenance.
- _5 value "Mig-6 as a novel negative feedback regulator of the epidermal growth factor receptor (EGFR) and potential tumor suppressor." provenance.
- _5 value "In addition to a general repressor activity on basal glucagon gene promoter activity of 30-50%, a specific 90% inhibition of Pax-6 mediated transactivation was observed. " provenance.
- _3 value "Numerous evidence has demonstrated the involvement in growth control of interferon (IFN) regulatory factor-1 (IRF-1), which shows tumor suppressor activity" provenance.
- _4 value "Finally, we found that p53 inactivation and c-myc expression, two cell cycle events regulated by Src during mitogenesis," provenance.
- _3 value "c-Abl function was dispensable in cells deficient in active p53 and inhibition of c-Abl reduced mitogen-induced c-myc expression. These data identify a novel function of cytoplasmic c-Abl in the signalling pathways regulating growth factor-induced c-myc expression and we propose the existence of a tyrosine kinase signalling cascade (PDGFR/c-Src/c-Abl) important for mitogenesis." provenance.
- _5 value "SPP-induced FHL2 activation is mediated by Rho GTPases, but not by the GTPases Cdc42, Rac1 or Ras, and depends on Rho-kinase." provenance.
- _5 value "coexpression of TAB1 and p38 enhanced autophosphorylation of p38" provenance.
- _5 value "Despite remarkable progress in dissecting the signaling pathways that are crucial for the metabolic effects of insulin, the molecular basis for the specificity of its cellular actions is not fully understood. One clue might lie in the spatial and temporal aspects of signaling. Recent evidence suggests that signaling molecules and pathways are localized to discrete compartments in cells by specific protein interactions. Also, the rapid termination of tyrosine or lipid phosphorylation by phosphatases or serine kinases might tightly control the strength of a signaling pathway, thus determining its effect on growth, differentiation and metabolism. Insulin is the most potent anabolic hormone known, promoting the synthesis and storage of carbohydrates, lipids and proteins and inhibiting their degradation and release back into the circulation. Decreased secretion of insulin, coupled with resistance to its actions, results in type 2 diabetes, a devastating disease that is reaching epidemic proportions [1]. Even in the absence of diabetes, insulin resistance is often associated with central obesity, hypertension, polycystic ovarian syndrome, dyslipidemia and atherosclerosis. At the cellular level, insulin action is characterized by diverse effects, including changes in vesicle trafficking, stimulation of protein kinases and phosphatases, promotion of cellular growth and differentiation and activation or repression of transcription. This complexity suggests that insulin action must involve multiple signaling pathways that diverge at or near the activation of its tyrosine kinase receptor. In fact, it is likely that even individual effects of the hormone require multiple signaling inputs. Evidence is emerging that the coordination of these pathways might be governed by their intracellular compartmentalization or duration of action. Here, we consider how temporal and spatial aspects of signal transduction play a crucial role in determining the specificity of insulin action, focusing on signal initiation from the receptor that is spatially segregated into discrete domains of the plasma membrane, as well as the mechanisms that determine the duration of individual signaling pathways. Together, these factors help to differentiate insulin from other hormones that share some of the same overall signaling properties. Divergent signaling pathways are initiated by insulin receptor substrates. The insulin receptor is a tyrosine kinase that catalyzes the phosphorylation of several intracellular substrates, including the insulin receptor substrate (IRS) proteins [2], GAB-1 [3], Shc [4], APS [5], p60DOK [6], SIRPS [7] and c-Cbl [8] (Fig. 1). Each of these substrates recruits a distinct subset of signaling proteins containing Src homology 2 (SH2) domains, which interact specifically with sequences surrounding the phosphotyrosine residue. Moreover, each of these substrates can be confined to distinct locations in the cell by specific sequences that direct interactions with other proteins or lipids. Most attention in the field of insulin receptor substrates has focused on the IRS family of proteins. Mice lacking the IRS-1 protein are insulin resistant but do not develop overt diabetes [9,10]. By contrast, animals lacking IRS-2 exhibit both impaired glucose tolerance and diabetes [11], which appears to result from a defect in insulin secretion as well as insulin resistance, presumably owing to decreased b-cell proliferation in the pancreas in the face of increased demand for insulin. Despite the similarity in structure and function, the apparent differences in phenotype between IRS1 and IRS2 knockout mice underscore a specific signaling specificity that probably results from their tissue distribution, subcellular location, activation–inactivation kinetics and combinatorial interactions with downstream effectors [12]. The tyrosine phosphorylation of IRS family members generates docking sites for sev..." provenance.
- _7 value "Despite remarkable progress in dissecting the signaling pathways that are crucial for the metabolic effects of insulin, the molecular basis for the specificity of its cellular actions is not fully understood. One clue might lie in the spatial and temporal aspects of signaling. Recent evidence suggests that signaling molecules and pathways are localized to discrete compartments in cells by specific protein interactions. Also, the rapid termination of tyrosine or lipid phosphorylation by phosphatases or serine kinases might tightly control the strength of a signaling pathway, thus determining its effect on growth, differentiation and metabolism. Insulin is the most potent anabolic hormone known, promoting the synthesis and storage of carbohydrates, lipids and proteins and inhibiting their degradation and release back into the circulation. Decreased secretion of insulin, coupled with resistance to its actions, results in type 2 diabetes, a devastating disease that is reaching epidemic proportions [1]. Even in the absence of diabetes, insulin resistance is often associated with central obesity, hypertension, polycystic ovarian syndrome, dyslipidemia and atherosclerosis. At the cellular level, insulin action is characterized by diverse effects, including changes in vesicle trafficking, stimulation of protein kinases and phosphatases, promotion of cellular growth and differentiation and activation or repression of transcription. This complexity suggests that insulin action must involve multiple signaling pathways that diverge at or near the activation of its tyrosine kinase receptor. In fact, it is likely that even individual effects of the hormone require multiple signaling inputs. Evidence is emerging that the coordination of these pathways might be governed by their intracellular compartmentalization or duration of action. Here, we consider how temporal and spatial aspects of signal transduction play a crucial role in determining the specificity of insulin action, focusing on signal initiation from the receptor that is spatially segregated into discrete domains of the plasma membrane, as well as the mechanisms that determine the duration of individual signaling pathways. Together, these factors help to differentiate insulin from other hormones that share some of the same overall signaling properties. Divergent signaling pathways are initiated by insulin receptor substrates. The insulin receptor is a tyrosine kinase that catalyzes the phosphorylation of several intracellular substrates, including the insulin receptor substrate (IRS) proteins [2], GAB-1 [3], Shc [4], APS [5], p60DOK [6], SIRPS [7] and c-Cbl [8] (Fig. 1). Each of these substrates recruits a distinct subset of signaling proteins containing Src homology 2 (SH2) domains, which interact specifically with sequences surrounding the phosphotyrosine residue. Moreover, each of these substrates can be confined to distinct locations in the cell by specific sequences that direct interactions with other proteins or lipids. Most attention in the field of insulin receptor substrates has focused on the IRS family of proteins. Mice lacking the IRS-1 protein are insulin resistant but do not develop overt diabetes [9,10]. By contrast, animals lacking IRS-2 exhibit both impaired glucose tolerance and diabetes [11], which appears to result from a defect in insulin secretion as well as insulin resistance, presumably owing to decreased b-cell proliferation in the pancreas in the face of increased demand for insulin. Despite the similarity in structure and function, the apparent differences in phenotype between IRS1 and IRS2 knockout mice underscore a specific signaling specificity that probably results from their tissue distribution, subcellular location, activation–inactivation kinetics and combinatorial interactions with downstream effectors [12]. The tyrosine phosphorylation of IRS family members generates docking sites for sev..." provenance.
- _5 value "Despite remarkable progress in dissecting the signaling pathways that are crucial for the metabolic effects of insulin, the molecular basis for the specificity of its cellular actions is not fully understood. One clue might lie in the spatial and temporal aspects of signaling. Recent evidence suggests that signaling molecules and pathways are localized to discrete compartments in cells by specific protein interactions. Also, the rapid termination of tyrosine or lipid phosphorylation by phosphatases or serine kinases might tightly control the strength of a signaling pathway, thus determining its effect on growth, differentiation and metabolism. Insulin is the most potent anabolic hormone known, promoting the synthesis and storage of carbohydrates, lipids and proteins and inhibiting their degradation and release back into the circulation. Decreased secretion of insulin, coupled with resistance to its actions, results in type 2 diabetes, a devastating disease that is reaching epidemic proportions [1]. Even in the absence of diabetes, insulin resistance is often associated with central obesity, hypertension, polycystic ovarian syndrome, dyslipidemia and atherosclerosis. At the cellular level, insulin action is characterized by diverse effects, including changes in vesicle trafficking, stimulation of protein kinases and phosphatases, promotion of cellular growth and differentiation and activation or repression of transcription. This complexity suggests that insulin action must involve multiple signaling pathways that diverge at or near the activation of its tyrosine kinase receptor. In fact, it is likely that even individual effects of the hormone require multiple signaling inputs. Evidence is emerging that the coordination of these pathways might be governed by their intracellular compartmentalization or duration of action. Here, we consider how temporal and spatial aspects of signal transduction play a crucial role in determining the specificity of insulin action, focusing on signal initiation from the receptor that is spatially segregated into discrete domains of the plasma membrane, as well as the mechanisms that determine the duration of individual signaling pathways. Together, these factors help to differentiate insulin from other hormones that share some of the same overall signaling properties. Divergent signaling pathways are initiated by insulin receptor substrates. The insulin receptor is a tyrosine kinase that catalyzes the phosphorylation of several intracellular substrates, including the insulin receptor substrate (IRS) proteins [2], GAB-1 [3], Shc [4], APS [5], p60DOK [6], SIRPS [7] and c-Cbl [8] (Fig. 1). Each of these substrates recruits a distinct subset of signaling proteins containing Src homology 2 (SH2) domains, which interact specifically with sequences surrounding the phosphotyrosine residue. Moreover, each of these substrates can be confined to distinct locations in the cell by specific sequences that direct interactions with other proteins or lipids. Most attention in the field of insulin receptor substrates has focused on the IRS family of proteins. Mice lacking the IRS-1 protein are insulin resistant but do not develop overt diabetes [9,10]. By contrast, animals lacking IRS-2 exhibit both impaired glucose tolerance and diabetes [11], which appears to result from a defect in insulin secretion as well as insulin resistance, presumably owing to decreased b-cell proliferation in the pancreas in the face of increased demand for insulin. Despite the similarity in structure and function, the apparent differences in phenotype between IRS1 and IRS2 knockout mice underscore a specific signaling specificity that probably results from their tissue distribution, subcellular location, activation–inactivation kinetics and combinatorial interactions with downstream effectors [12]. The tyrosine phosphorylation of IRS family members generates docking sites for sev..." provenance.
- _6 value "Once phosphorylated, Cbl can recruit the SH2-containing adaptor protein CrkII to lipid rafts, along with the GEF C3G. C3G then appears to activate the Rho family GTPase TC10. This small GTP-binding protein is produced in fat and muscle and can be acutely activated by insulin in a CAP-dependent but PdtIns-3-kinase-independent manner. Activation of TC10 is specific for insulin, and disruption of its activation blocks insulin-stimulated glucose transport and Glut4 translocation." provenance.