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)

Oxidative stress is involved in several pathological conditions, including diabetes. Reactive oxygen species (ROS) have been demonstrated to act as second messengers for several hormones and cytokines, including insulin (INS). The effect of Cu(2+)-oxidized LDL (CuLDL) on INS-induced generation of ROS and on INS signaling was investigated on cultured human fibroblasts. Intracellular ROS generation was observed either in CuLDL- or in INS-treated cells. Moreover, CuLDL and INS had an additive effect on ROS formation in human fibroblasts. CuLDL by itself increased the phosphorylation of ERK without affecting the PKB/Akt phosphorylation. CuLDL also stimulated the DNA binding activities of the transcription factors AP1 and NFkappaB. However, CuLDL dose-dependently prevented the INS-signaling pathway, by inhibiting the INS-induced phosphorylation of the signaling kinases ERK and PKB/Akt and the INS-induced activation of the transcription factors AP1 and NFkappaB. Finally, the lipophilic antioxidant Vitamin E (Vit E) partially restored all the studied signaling events initiated by INS and impaired after pretreatment with CuLDL. These studies demonstrate that the oxidative stress generated by CuLDL has a negative effect on the INS-signaling pathway, independently of the INS-induced generation of ROS. Thus, oxidized LDL might be involved not only in atherosclerosis, as it is commonly admitted, but also in the INS-resistance observed in type 2 diabetes mellitus.
Atherosclerosis 2004 Jul
PMID:Inhibition of insulin signaling by oxidized low density lipoprotein. Protective effect of the antioxidant Vitamin E. 1518 43

Smooth muscle cell (SMC) proliferation is suppressed in intact blood vessels but stimulated in atherosclerosis, restenosis after angioplasty, and vein graft disease. The cyclin-dependent kinase inhibitors, including p27(Kip1), play important roles in maintaining SMC quiescence. Levels of p27(Kip1) are dependent on attachment to and the composition of the extracellular matrix (ECM). Here we sought to elucidate mechanisms underlying the ECM-dependent regulation of p27(Kip1) and hence, SMC proliferation. Serum stimulation decreased p27(Kip1) levels in isolated SMC but not in rat aorta. The effect was post-translational and mediated by proteasomal degradation. We studied the S-phase-associated kinase protein-2 (Skp-2), an F-box protein involved in ubiquitination and proteasome-mediated degradation. Skp-2 protein is strongly induced by serum from undetectable levels in isolated SMCs but remains undetectable in aorta; Skp-2 mRNA is also lower in aorta. Overexpression of wild-type Skp-2 in SMCs decreased p27(Kip1) levels, whereas dominant negative F-box deleted mutant (DeltaF-Skp-2) Skp-2 increased p27(Kip1) levels. Furthermore, hyperphosphorylation of retinoblastoma protein and SMC proliferation were also reciprocally affected by wild-type and dominant negative Skp-2. Skp-2 expression was absolutely dependent on cell attachment to the ECM and was inhibited by laminin and type-1 fibrillar collagen but increased by fibronectin. Expression of Skp-2 protein, but not mRNA, was associated with focal adhesion kinase (FAK) activity and inhibited by overexpression of FAK-related non-kinase and a dominant negative FAK(Y397F) mutant. Furthermore, the inhibition of Skp-2 expression by dominant negative FAK was reversed by the proteasome inhibitor MG-132. Taken together, these data demonstrate that the vascular ECM controls SMC proliferation via FAK-dependent regulation of Skp-2 protein stability.
...
PMID:Focal adhesion kinase (FAK)-dependent regulation of S-phase kinase-associated protein-2 (Skp-2) stability. A novel mechanism regulating smooth muscle cell proliferation. 1520 31

Variation in the APOA5 gene has been shown to be associated with triglyceride levels in several independent population studies. It was our objective to determine if a relationship existed between selected genotypes or haplotypes of the APOA5 gene and findings on selective coronary angiography (SCA) in an independent cohort. The Vancouver SCA Cohort consists of individuals referred for angiography between 1993 and 1995. DNA was extracted from 537 patients and analyzed for the -1131T>C and the c.56C>G polymorphisms which define three common haplotypes of the APOA5 gene. Plasma triglycerides and the fractional esterification rate in apoB-depleted lipoproteins (FER(HDL)), an index of high-density lipoprotein (HDL) composition, were significantly higher (P = 0.01 and P = 0.001, respectively), and HDL cholesterol (HDL-C) was significantly lower (P = 0.03) in Caucasians with genotypes containing the minor allele of the -1131T>C polymorphism compared to the homozygotes for the major allele. However, there was no relationship between the c.56C>G polymorphism of the APOA5 gene and any of the measured lipid and lipoprotein parameters. Subjects homozygous for the common haplotype APOA5*1 had decreased triglyceride levels and FER(HDL) (P = 0.04 and P < 0.001, respectively) and increased HDL-C levels (P = 0.01) compared to subjects with all other haplogenotypes. Multivariate linear regression analysis indicated that the -1131T>C polymorphism remained an independent predictor of triglyceride, HDL-C, and FER(HDL) following adjustment of several variables including age, gender, body mass index, diabetes, lipid lowering and beta-blocker medication. The APOA5*1/*1 haplogenotype remained an independent predictor of HDL-C and FER(HDL) following adjustment of the same variables. The relationship between APOA5 genotype or haplogenotype and FER(HDL) remained significant even after the addition of both HDL-C and triglyceride to the model. However, there was no association between APOA5 gene polymorphisms or haplotypes and coronary artery disease as determined by angiography.
Atherosclerosis 2004 Sep
PMID:APOA5 gene polymorphism modulates levels of triglyceride, HDL cholesterol and FERHDL but is not a risk factor for coronary artery disease. 1530 90

The effects of four natural tocopherols on the proliferation and signaling pathways were examined in the human mastocytoma cell line (HMC-1). The four tocopherols inhibited HMC-1 cell proliferation with different potency (delta > alpha = gamma > beta). Growth inhibition correlated with the reduction of PKB (protein kinase B) phosphorylation by the different tocopherols. The reduction of PKB phosphorylation led to a decrease of its activity, as judged from a parallel reduction of GSKalpha/beta phosphorylation. The translocation of PKB to the membrane, as a response to receptor stimulation by NGFbeta, is also prevented by treatment with tocopherols. In the presence of PKC or PP2A inhibitors, the reduction of PKB phosphorylation by tocopherols was still observed, thus excluding the direct involvement of these enzymes. Other pathways, such as the Ras-stimulated ERK1/2 (extracellular signal responsive kinase) pathway, were not affected by tocopherol treatment. The tocopherols did not significantly change oxidative stress in HMC-1 cells, suggesting that the observed effects are not the result of a general reduction of oxidative stress. Thus, the tocopherols interfere with PKB phosphorylation and reduce proliferation of HMC-1 cells, possibly by modulating either phosphatidylinositol 3-kinase, a kinase phosphorylating PKB (PDK1/2), or a phosphatase that dephosphorylates it. Inhibition of proliferation and PKB signaling in HMC-1 cells by vitamin E suggests a role in preventing diseases with mast cell involvement, such as allergies, atherosclerosis, and tumorigenesis.
...
PMID:Inhibition of HMC-1 mast cell proliferation by vitamin E: involvement of the protein kinase B pathway. 1538 41

A chronic increase in systemic levels of acute-phase reactants contributes to the development of insulin resistance and associated disorders such as cardiovascular disease. Recently, serum amyloid A3 (SAA3) has been characterized as an adipocyte-secreted acute-phase reactant, expression of which is dramatically increased in insulin resistance and obesity. To further clarify expression and regulation of this adipocytokine in fat, SAA3 mRNA was measured by quantitative real-time reverse transcriptase PCR during differentiation of 3T3-L1 adipocytes and after treatment with various hormones known to induce insulin resistance and contribute to atherosclerosis. SAA3 mRNA was dramatically induced up to 77-fold during differentiation of 3T3-L1 preadipocytes. Furthermore, 100 nM dexamethasone and 30 ng/ml interleukin (IL)-6 induced SAA3 mRNA by up to 11- and 4.8-fold, respectively, in a time-dependent fashion with significant stimulation observed at concentrations as low as 10 nM dexamethasone and 1 ng/ml IL-6. In contrast, insulin, isoproterenol and growth hormone did not influence SAA3 synthesis. Inhibitor studies suggested that the positive effect of IL-6 on SAA3 expression is at least in part mediated by Janus kinase 2. Taken together, our results show a differential regulation of SAA3 by glucocorticoids and IL-6 supporting an integrative role of this acute-phase reactant in the pathogenesis of insulin resistance and its link to obesity and cardiovascular disease.
...
PMID:Serum amyloid A3 expression is stimulated by dexamethasone and interleukin-6 in 3T3-L1 adipocytes. 1559 Sep 82

The hypertrophy of vascular smooth muscle cells (VSMCs) is critical in vascular remodeling associated with hypertension, atherosclerosis, and restenosis. Recently, leptin has appeared to play a pivotal role in vascular remodeling. However, the mechanism by which leptin induces hypertrophy in vascular smooth muscle cells is still unknown. We studied the role of leptin as a potential hypertrophic factor in rat VSMCs. In the present study, leptin significantly increased [(3)H]leucine incorporation and the total protein/DNA ratio in VSMCs. The maximal hypertrophic effect was at 100ng/ml of leptin. Leptin induced phosphorylation and activation of p38 mitogen-activated protein (p38 MAP) kinase and of signal transducers and activators of transcription 3 in a concentration- and time-dependent manner. A p38 MAP kinase inhibitor SB203580 significantly inhibited leptin-induced hypertrophy, AG490 (a JAK2 inhibitor) partially inhibited it, and other MAP kinase inhibitors, PD98059 (an ERK inhibitor) and SP600125 (a JNK inhibitor), had no effect. These results indicate that leptin directly stimulates cellular hypertrophy via p38 MAP kinase in rat VSMCs.
...
PMID:Leptin induces hypertrophy via p38 mitogen-activated protein kinase in rat vascular smooth muscle cells. 1572 Dec 67

Extracellular nucleotides bind to type-2 purinergic/pyrimidinergic (P2) receptors that mediate various responses, such as cell activation, proliferation and apoptosis, implicated in inflammatory processes. The role of P2 receptors and their associated signal transduction pathways in endothelial cell responses has not been fully investigated. Here, it is shown that stimulation of human umbilical vein endothelial cells (HUVEC) with extracellular ATP or UTP increased intracellular free calcium ion concentrations ([Ca(2+)](i)), induced phosphorylation of focal adhesion kinase (FAK), p130(cas) and paxillin, and caused cytoskeletal rearrangements with consequent cell migration. Furthermore, UTP increased migration of HUVEC in a phosphatidylinositol 3-kinase (PI3-K)-dependent manner. BAPTA or thapsigargin inhibited the extracellular nucleotide-induced increase in [Ca(2+)](i), a response crucial for both FAK phosphorylation and cell migration. Furthermore, long-term exposure of HUVEC to ATP and UTP, agonists of the G protein-coupled P2Y2 and P2Y4 receptor subtypes, caused upregulation of alpha(v) integrin expression, a cell adhesion molecule known to directly interact with P2Y2 receptors. Our results suggest that extracellular nucleotides modulate signaling pathways in HUVEC influencing cell functions, such as cytoskeletal changes, cellular adhesion and motility, typically associated with integrin-activation and the action of growth factors. We propose that P2Y2 and possibly P2Y4 receptors mediate those responses that are important in vascular inflammation, atherosclerosis and angiogenesis.
...
PMID:Modulation of endothelial cell migration by extracellular nucleotides: involvement of focal adhesion kinase and phosphatidylinositol 3-kinase-mediated pathways. 1584 22

Recent clinical studies have revealed that increased serum triglyceride (TG) levels are closely related to atherosclerosis, independently of serum levels of high-density lipoproteins (HDL) and low-density lipoproteins (LDL). Among triglyceride-rich lipoproteins (TRLs), remnant lipoproteins (RLPs) are considered to be atherogenic and an independent coronary risk factor. We previously reported that monocytes cultured in the presence of RLPs increased their adhesion to vascular endothelial cells. The underlying mechanism involved activation of RhoA, a member of small GTP binding proteins, resulting in activation of focal adhesion kinase (FAK) and s1-integrin. It is also known that RLPs enter vessel walls. In another study, we reported that RLPs induced smooth muscle cell (SMC) proliferation, independently of oxidative stress. Recently, we identified the molecular mechanisms, in which RLPs from hypertriglyceridemic patients stimulated SMC proliferation via epidermal growth factor (EGF) receptor transactivation and heparin-binding EGF-like growth factor (HB-EGF) shedding. More recently, we reported that apoB48 receptor was involved in RLP-induced foam cell formation in macrophages. The current review focused on the molecular mechanisms for the atherogenicity of RLPs.
...
PMID:Remnant lipoproteins and atherogenesis. 1594 16

Type 2 diabetics have an increased risk of developing atherosclerosis, suggesting the mechanisms that cause this disease are enhanced by insulin resistance. In this study we examined the effects of gene knock-out (KO) of lipocalin-type prostaglandin D(2) synthase (L-PGDS), a protein found at elevated levels in type 2 diabetics, on diet-induced glucose tolerance and atherosclerosis. Our results show that L-PGDS KO mice become glucose-in-tolerant and insulin-resistant at an accelerated rate when compared with the C57BL/6 control strain. Adipocytes were significantly larger in the L-PGDS KO mice compared with controls on the same diets. Cell culture data revealed significant differences between insulin-stimulated mitogen-activated protein kinase phosphatase-2, protein-tyrosine phosphatase-1D, and phosphorylated focal adhesion kinase expression levels in L-PGDS KO vascular smooth muscle cells and controls. In addition, only the L-PGDS KO mice developed nephropathy and an aortic thickening reminiscent to the early stages of atherosclerosis when fed a "diabetogenic" high fat diet. We conclude that L-PGDS plays an important role regulating insulin sensitivity and atherosclerosis in type 2 diabetes and may represent a novel model of insulin resistance, atherosclerosis, and diabetic nephropathy.
...
PMID:Accelerated glucose intolerance, nephropathy, and atherosclerosis in prostaglandin D2 synthase knock-out mice. 1597 May 90

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. In vascular diseases, such as atherosclerosis, inflammation plays an important role in the pathogenesis of the disease. We examined the role of LPL in modulating tumor necrosis factor-alpha (TNF-alpha)- and interferon-gamma (IFN-gamma)-mediated inflammatory cytokine signal transduction pathways in human aortic endothelial cells (HAECs). LPL significantly suppressed TNF-alpha-induced gene expression, and this suppression was reversed by tetrahydrolipstatin and heparinase. In contrast, LPL synergistically enhanced IFN-gamma-induced gene expression in HAECs. To elucidate the molecular mechanisms of LPL action, we investigated the role of transcription factors nuclear factor kappa B (NF-kappaB) and signal transducer and activator of transcription factor 1 (Stat1). The anti-inflammatory response of LPL in suppressing TNF-alpha-induced gene expression was a result of its inhibition of NF-kappaB activity by the abrogation of IkappaB-alpha degradation and phosphorylation of the p65 subunit. Although LPL alone had no effect on Stat1 activation, LPL enhanced IFN-gamma-induced phosphorylation of Stat1 on tyrosine 701 and serine 727, as well as Stat1-mediated transactivation. The synergistic effect of LPL on IFN-gamma-induced Stat1 activation was mediated by enhanced activation of the tyrosine kinase JAK2 and was abrogated by LY294002, a specific inhibitor of the phosphatidylinositol 3'-kinase pathway. Our studies indicate that LPL has differential effects on several inflammatory pathways known to be important in atherosclerosis.
...
PMID:Differential effects of lipoprotein lipase on tumor necrosis factor-alpha and interferon-gamma-mediated gene expression in human endothelial cells. 1599 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---