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)

In patients with chronic heart failure (CHF) increased plasma concentrations of proinflammatory cytokines are found. For example, the plasma interleukin-6 (IL-6) concentration correlates with disease severity. Beside IL-6 cardiotrophin-1 (CT-1), a member of the IL-6 superfamily, is also increased in CHF. We examined whether CT-1 is able to induce IL-6 in human umbilical vein endothelial cells (HUVEC) and characterised the underlying pathway. IL-6 mRNA was determined by real-time PCR and by RT-PCR in HUVEC which were stimulated with different CT-1 concentrations and for different time periods. IL-6 concentration in the supernatant was determined by ELISA. For the pathway determination following inhibitors were used: piceatannol (signal transducer and activation of transcription (STAT)3 phosphorylation), wortmannin (phosphatiylinositol 3-kinase (PI3K)), SB203580 (p38 mitogen-activated protein kinase (MAPK)), AG490 (Janus kinase (JAK)2), PD98059 (mitogen-activated protein kinase kinase (MEK) 1/2), parthenolide (nuclear factor kappaB) and cycloheximide (protein biosynthesis). CT-1 caused a concentration- and time-dependent increase in IL-6 mRNA in HUVEC with a maximal induction seen after 6 h (2-fold compared to control) with 100 ng/ml CT-1. In the supernatant of HUVEC a concentration- and time-dependent increase of IL-6 protein was found. A maximum effect with 100 ng/ml CT-1 was found after 24 h (11-fold compared to control). AG490, SB203580, piceatannol, parthenolide and cycloheximide inhibit CT-1 induced IL-6 mRNA and protein expression whereas wortmannin and PD98059 did not inhibit IL-6 expression. CT-1 induced both IL-6 mRNA and protein in a concentration- and time-dependent manner in HUVEC. The underlying pathway includes activation of JAK2, STAT3, p38 and NFkappaB. CT-1 induced IL-6 expression and requires protein synthesis and IL-6 is not stored intracellularly. We speculate that in CHF CT-1 might be in part responsible for increased IL-6 plasma concentrations. Modulation of the CT-1 pathway may be a further strategy in CHF treatment.
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PMID:Cardiotrophin-1 induces interleukin-6 synthesis in human umbilical vein endothelial cells. 1719 93

mda-9/Syntenin is a scaffolding PDZ domain-containing protein overexpressed in multiple human cancers that functions as a positive regulator of melanoma metastasis. Using a normal immortal human melanocyte cell line and weakly and highly metastatic human melanoma cell lines, we presently show that mda-9/syntenin initiates a signaling cascade that activates nuclear factor-kappaB (NF-kappaB) in human melanoma cells. As a consequence of elevated mda-9/syntenin expression, tumor cell growth and motility, fundamental components of tumor cell invasion and metastatic spread of melanoma cells, are enhanced through focal adhesion kinase (FAK)-induced and p38 mitogen-activated protein kinase (MAPK)-induced activation of NF-kappaB. Inhibiting mda-9/syntenin, using an adenovirus expressing antisense mda-9/syntenin, NF-kappaB, using an adenovirus expressing a mutant super-repressor of IkappaBalpha, or FAK, and using a dominant-negative mutant of FAK (FRNK), blocks melanoma cell migration, anchorage-independent growth, and invasion. Downstream signaling changes mediated by mda-9/syntenin, which include activation of FAK, p38 MAPK, and NF-kappaB, promote induction of membrane-type matrix metalloproteinase-1 that then activates pro-MMP-2-promoting migration and extracellular matrix invasion of melanoma cells. These results highlight the importance of mda-9/syntenin as a key component of melanoma metastasis providing a rational molecular target for potentially intervening in the metastatic process.
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PMID:mda-9/Syntenin regulates the metastatic phenotype in human melanoma cells by activating nuclear factor-kappaB. 1730 24

In the present study, a novel synthetic compound 4-(2-(cyclohex-2-enylidene)hydrazinyl)quinolin-2(1H)-one (CYL-4d) was found to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production without affecting cell viability or enzyme activity of expressed inducible NO synthase (iNOS) in RAW 264.7 macrophages. CYL-4d exhibited parallel inhibition of LPS-induced expression of iNOS protein, iNOS mRNA and iNOS promoter activity in the same concentration range. LPS-induced activator protein-1 (AP-1) DNA binding, AP-1-dependent reporter gene activity and c-Jun nuclear translocation were all markedly inhibited by CYL-4d with similar efficacy, whereas CYL-4d produced a weak inhibition of nuclear factor-kappaB (NF-kappaB) DNA binding, NF-kappaB-dependent reporter gene activity and p65 nuclear translocation without affecting inhibitory factor-kappa B alpha (I kappa B alpha) degradation. CYL-4d had no effect on the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and its upstream activator MAPK kinase (MEK) 3, whereas it significantly attenuated the phosphorylation of c-Jun, c-Jun NH(2)-terminal kinase (JNK) and its upstream activator MEK4 in a parallel concentration-dependent manner. Other Toll-like receptors (TLRs) ligands (peptidoglycans, double-stranded RNA, and oligonucleotide containing unmethylated CpG motifs)-induced iNOS protein expression were also inhibited by CYL-4d. Furthermore, the NO production from BV-2 microglial cells as well as rat alveolar macrophages in response to LPS was diminished by CYL-4d. These results indicate that the blockade of NO production by CYL-4d in LPS-stimulated RAW 264.7 cells is attributed mainly to interference in the MEK4-JNK-AP-1 signaling pathway. CYL-4d inhibition of NO production is not restricted to TLR4 activation and immortalized macrophage-like cells.
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PMID:Inhibition of lipopolysaccharide-stimulated NO production by a novel synthetic compound CYL-4d in RAW 264.7 macrophages involving the blockade of MEK4/JNK/AP-1 pathway. 1737 90

Secondary resistance to hormonal therapy for breast cancer commonly develops after an initial response to tamoxifen or aromatase inhibitors. Agents to abrogate these adaptive changes would substantially enhance the long-term benefits of hormonal therapy. Our studies with a stilbene derivative called TMS (2,3',4,5'-tetramethoxystilbene) identified unexpected effects with potential utility for treatment of breast tumors secondarily resistant to hormonal therapy. TMS was originally developed as an inhibitor of cytochrome P450 1B1 to block the conversion of estradiol to 4-OH-estradiol. While studying this agent in three models of hormone resistance, we detected direct antitumor effects not related to its role as an inhibitor of catecholestrogens. During examination of the mechanisms involved, we showed that treatment with 3 micromol/L TMS for 24 h inhibited tubulin polymerization and microtubule formation, caused a cell cycle block at the G2-M phase, and induced apoptosis. TMS also inhibited activated focal adhesion kinase (FAK), Akt, and mammalian target of rapamycin (mTOR) and stimulated c-jun-NH2-kinase and p38 mitogen-activated protein kinase activity. With respect to antitumor effects, TMS at a concentrations of 0.2 to 0.3 micromol/L inhibited the growth of long-term tamoxifen-treated MCF-7 cells by 80% and fulvestrant-treated MCF-7 cells by 70%. In vivo studies, involving 8 weeks of treatment with TMS via a 30-mg s.c. implant, reduced tumor volume of tamoxifen-resistant MCF-7 breast cancer xenografts by 53%. Our data suggest that TMS is a promising therapeutic agent because of its unique ability to block several pathways involved in the development of hormone resistance.
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PMID:Effects of tetramethoxystilbene on hormone-resistant breast cancer cells: biological and biochemical mechanisms of action. 1757 38

Ca2+ signalling plays an important role in excitation-contraction coupling and the resultant force output of skeletal muscle. It is also known to play a crucial role in modulating both short- and long-term muscle cellular phenotypic adaptations associated with these events. Ca2+ signalling via the Ca2+/calmodulin (CaM)-dependent phosphatase calcineurin (CnA) and via Ca2+/CaM-dependent kinases, such as CaMKI and CaMKII, is known to regulate hypertrophic growth in response to overload, to direct slow versus fast fibre gene expression, and to contribute to mitochondrial biogenesis. The CnA- and CaMK-dependent regulation of the downstream transcription factors nuclear factor of activated T cells (NFAT) and myocyte-specific enhancer factor 2 are known to activate muscle-specific genes associated with a slower, more oxidative fibre phenotype. We have also recently shown the expression of utrophin A, a cytoskeletal protein that accumulates at the neuromuscular junction and plays a role in maturation of the postsynaptic apparatus, to be regulated by CnA-NFAT and Ca2+/CaM signalling. This regulation is fibre-type specific and potentiated by interactions with the transcriptional regulators and coactivators GA binding protein (also known as nuclear respiratory factor 2) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha. Another downstream target of CnA signalling may be myostatin, a transforming growth factor-beta family member that is a negative regulator of muscle growth. While the list of the downstream targets of CnA/NFAT- and Ca2+/CaM-dependent signalling is emerging, the precise interaction of these pathways with the Ca2+-independent pathways p38 mitogen-activated protein kinase, extracellular signal-regulated kinases 1 and 2, phosphoinositide-3 kinase, and protein kinase B (Akt/PKB) must also be considered when deciphering fibre responses and plasticity to altered contractile load.
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PMID:Ca2+/calmodulin-based signalling in the regulation of the muscle fibre phenotype and its therapeutic potential via modulation of utrophin A and myostatin expression. 1805 17

We demonstrated previously that, in mice with chronic angiotensin II-dependent hypertension, gp91phox-containing NADPH oxidase is not involved in the development of high blood pressure, despite being important in redox signaling. Here we sought to determine whether a gp91phox homologue, Nox1, may be important in blood pressure elevation and activation of redox-sensitive pathways in a model in which the renin-angiotensin system is chronically upregulated. Nox1-deficient mice and transgenic mice expressing human renin (TTRhRen) were crossed, and 4 genotypes were generated: control, TTRhRen, Nox1-deficient, and TTRhRen Nox1-deficient. Blood pressure and oxidative stress (systemic and renal) were increased in TTRhRen mice (P<0.05). This was associated with increased NADPH oxidase activation. Nox1 deficiency had no effect on the development of hypertension in TTRhRen mice. Phosphorylation of c-Src, mitogen-activated protein kinases, and focal adhesion kinase was significantly increased 2- to 3-fold in kidneys from TTRhRen mice. Activation of c-Src, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and focal adhesion kinase but not of extracellular signal regulated kinase 1/2 or extracellular signal regulated kinase 5, was reduced in TTRhRen/Nox1-deficient mice (P<0.05). Expression of procollagen III was increased in TTRhRen and TTRhRen/Nox1-deficient mice versus control mice, whereas vascular cell adhesion molecule-1 was only increased in TTRhRen mice. Our findings demonstrate that, in Nox1-deficient TTRhRen mice, blood pressure is elevated despite reduced NADPH oxidase activation, decreased oxidative stress, and attenuated redox signaling. Our results suggest that Nox1-containing NADPH oxidase plays a key role in the modulation of systemic and renal oxidative stress and redox-dependent signaling but not in the elevation of blood pressure in a model of chronic angiotensin II-dependent hypertension.
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PMID:Renal redox-sensitive signaling, but not blood pressure, is attenuated by Nox1 knockout in angiotensin II-dependent chronic hypertension. 1819 61

Integrin-mediated adhesion to the extracellular matrix plays a fundamental role in tumor metastasis. Salvicine, a novel diterpenoid quinone compound identified as a nonintercalative topoisomerase II poison, possesses a broad range of antitumor and antimetastatic activity. Here, the mechanism underlying the antimetastatic capacity of salvicine was investigated by exploring the effect of salvicine on integrin-mediated cell adhesion. Salvicine inhibited the adhesion of human breast cancer MDA-MB-435 cells to fibronectin and collagen without affecting nonspecific adhesion to poly-l-lysine. The fibronectin-dependent formation of focal adhesions and actin stress fibers was also inhibited by salvicine, leading to a rounded cell morphology. Furthermore, salvicine down-regulated beta(1) integrin ligand affinity, clustering and signaling via dephosphorylation of focal adhesion kinase and paxillin. Conversely, salvicine induced extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) phosphorylation. The effect of salvicine on beta(1) integrin function and cell adhesion was reversed by U0126 and SB203580, inhibitors of MAPK/ERK kinase 1/2 and p38 MAPK, respectively. Salvicine also induced the production of reactive oxygen species (ROS) that was reversed by ROS scavenger N-acetyl-l-cysteine. N-acetyl-l-cysteine additionally reversed the salvicine-induced activation of ERK and p38 MAPK, thereby maintaining functional beta(1) integrin activity and restoring cell adhesion and spreading. Together, this study reveals that salvicine activates ERK and p38 MAPK by triggering the generation of ROS, which in turn inhibits beta(1) integrin ligand affinity. These findings contribute to a better understanding of the antimetastatic activity of salvicine and shed new light on the complex roles of ROS and downstream signaling molecules, particularly p38 MAPK, in the regulation of integrin function and cell adhesion.
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PMID:Salvicine inactivates beta 1 integrin and inhibits adhesion of MDA-MB-435 cells to fibronectin via reactive oxygen species signaling. 1831 80

Dietary genistein has been linked to lower prostate cancer (PCa) mortality. Metastasis is the ultimate cause of death from PCa. Cell detachment and invasion represent early steps in the metastatic cascade. We had shown that genistein inhibits PCa cell detachment and cell invasion in vitro. Genistein-mediated inhibition of activation of focal adhesion kinase (FAK) and of the p38 mitogen-activated protein kinase (MAPK)-heat shock protein 27 (HSP27) pathway has been shown by us to regulate PCa cell detachment and invasion effects, respectively. To evaluate the antimetastatic potential of genistein, we developed an animal model suited to evaluating antimetastatic drug efficacy. Orthotopically implanted human PC3-M PCa cells formed lung micrometastasis by 4 weeks in >80% of inbred athymic mice. Feeding mice dietary genistein before implantation led to blood concentrations similar to those measured in genistein-consuming men. Genistein decreased metastases by 96%, induced nuclear morphometric changes in PC3-M cells indicative of increased adhesion (i.e., decreased detachment) but did not alter tumor growth. Genistein increased tumor levels of FAK, p38 MAPK, and HSP27 "promotility" proteins. However, the ratio of phosphorylated to total protein trended downward, indicating a failure to increase relative amounts of activated protein. This study describes a murine model of human PCa metastasis well suited for testing antimetastatic drugs. It shows for the first time that dietary concentrations of genistein can inhibit PCa cell metastasis. Increases in promotility proteins support the notion of cellular compensatory responses to antimotility effects induced by therapy. Studies of antimetastatic efficacy in man are warranted and are under way.
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PMID:Dietary genistein inhibits metastasis of human prostate cancer in mice. 1833 85

The scaffold PDZ-domain containing protein mda-9/syntenin functions as a positive regulator of cancer cell progression in human melanoma and other tumors. mda-9/Syntenin regulates cell motility and invasion by altering defined biochemical and signaling pathways, including focal adhesion kinase (FAK), p38 mitogen-activated protein kinase (MAPK) and NF-kappaB, but precisely how mda-9/syntenin organizes these multiprotein signaling complexes is not well understood. Using a clinically relevant human melanoma model, we demonstrate that mda-9/syntenin physically interacts with c-Src and this communication correlates with an increase in FAK/c-Src complex formation and c-Src activation. Inhibiting mda-9/syntenin, using an adenovirus expressing antisense mda-9/syntenin or addition of c-Src siRNA, suppresses melanoma cell migration, anchorage-independent growth, and spontaneous tumor cell dissemination in vivo in a human melanoma animal metastasis model. These data are compatible with a model wherein interaction of MDA-9/syntenin with c-Src promotes the formation of an active FAK/c-Src signaling complex, leading to enhanced tumor cell invasion and metastatic spread. These provocative findings highlight mda-9/syntenin and its interacting partners as promising therapeutic targets for intervention of metastasis.
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PMID:mda-9/Syntenin promotes metastasis in human melanoma cells by activating c-Src. 1883 67

Reactive oxygen species (ROS) have been implicated in vascular smooth muscle cell (VSMC) apoptosis, a hallmark of advanced atherosclerotic lesions. Transient oxidation and inactivation of protein-tyrosine phosphatases play a critical role in cellular response to ROS production. However, the function of leukocyte antigen-related (LAR) protein-tyrosine phosphatase in ROS signaling is not known. To determine the expression of LAR in ROS-induced apoptosis, we investigated hydrogen peroxide-induced cell death and signaling in aortic VSMCs from wild-type and LAR(-/-) mice. Histone-associated DNA fragmentation and caspase-3/7 activity were significantly enhanced, mitochondrial membrane integrity was compromised, and cell viability was significantly decreased following H(2)O(2) treatment in LAR(-/-) VSMCs compared with wild-type cells. Stronger and sustained increase in autophosphorylation and activity of Fyn, an Src family tyrosine kinase, was observed in LAR(-/-) cells compared with wild-type cells following H(2)O(2) treatment. LAR binds to activated Fyn in H(2)O(2)-treated VSMCs, and recombinant LAR dephosphorylates phosphorylated-Fyn in vitro. In addition, LAR deficiency enhanced H(2)O(2)-induced phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and p38 mitogen-activated protein kinase (MAPK). PP2, a Fyn-specific inhibitor, blocked JAK2, STAT3, and p38 MAPK activation and significantly attenuated apoptosis induced by H(2)O(2). AG490, a JAK2-specific inhibitor, significantly attenuated H(2)O(2)-induced apoptosis, and blocked H(2)O(2)-induced activation of STAT3, but not p38 MAPK in both wild-type and LAR(-/-) VSMCs. Attenuation of Fyn expression by short hairpin RNA significantly decreased H(2)O(2)-induced downstream signaling and apoptosis in VSMCs. Together, these data indicate that LAR regulates Fyn/JAK2/STAT3 and Fyn/p38 MAPK pathways involved in ROS-induced apoptosis.
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PMID:Leukocyte antigen-related protein tyrosine phosphatase negatively regulates hydrogen peroxide-induced vascular smooth muscle cell apoptosis. 1885 10


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