Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although human atherosclerosis is associated with aging, direct evidence of cellular senescence and the mechanism of senescence in vascular smooth muscle cells (VSMCs) in atherosclerotic plaques is lacking. We examined normal vessels and plaques by histochemistry, Southern blotting, and fluorescence in situ hybridization for telomere signals. VSMCs in fibrous caps expressed markers of senescence (senescence-associated beta-galactosidase [SAbetaG] and the cyclin-dependent kinase inhibitors [cdkis] p16 and p21) not seen in normal vessels. In matched samples from the same individual, plaques demonstrated markedly shorter telomeres than normal vessels. Fibrous cap VSMCs exhibited markedly shorter telomeres compared with normal medial VSMCs. Telomere shortening was closely associated with increasing severity of atherosclerosis. In vitro, plaque VSMCs demonstrated morphological features of senescence, increased SAbetaG expression, reduced proliferation, and premature senescence. VSMC senescence was mediated by changes in cyclins D/E, p16, p21, and pRB, and plaque VSMCs could reenter the cell cycle by hyperphosphorylating pRB. Both plaque and normal VSMCs expressed low levels of telomerase. However, telomerase expression alone rescued plaque VSMC senescence despite short telomeres, normalizing the cdki/pRB changes. In vivo, plaque VSMCs exhibited oxidative DNA damage, suggesting that telomere damage may be induced by oxidant stress. Furthermore, oxidants induced premature senescence in vitro, with accelerated telomere shortening and reduced telomerase activity. We conclude that human atherosclerosis is characterized by senescence of VSMCs, accelerated by oxidative stress-induced DNA damage, inhibition of telomerase and marked telomere shortening. Prevention of cellular senescence may be a novel therapeutic target in atherosclerosis.
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PMID:Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. 1679 90

Atherosclerotic plaque develops at sites of disturbed flow. We previously showed that flow activates endothelial cell integrins, which then bind to the subendothelial extracellular matrix (ECM), and, in cells on fibronectin or fibrinogen, trigger nuclear factor-kappaB activation. Additionally, fibronectin and fibrinogen are deposited into the subendothelial ECM at atherosclerosis-prone sites at early times. We now show that flow activates ECM-specific signals that establish patterns of integrin dominance. Flow induced alpha2beta1 activation in cells on collagen, but not on fibronectin or fibrinogen. Conversely, alpha5beta1 and alphavbeta3 are activated on fibronectin and fibrinogen, but not collagen. Failure of these integrins to be activated on nonpermissive ECM is because of active suppression by the integrins that are ligated. Protein kinase A is activated specifically on collagen and suppresses flow-induced alphavbeta3 activation. Alternatively, protein kinase Calpha is activated on fibronectin and mediates alpha2beta1 suppression. Thus, integrins actively cross-inhibit through specific kinase pathways. These mechanisms may determine cellular responses to complex extracellular matrices.
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PMID:Matrix-specific suppression of integrin activation in shear stress signaling. 1692 57

The trichothecene mycotoxin deoxynivalenol (DON), a frequent contaminant of cereal grains, is known to dysregulate mucosal and systemic immunity. In this study, we tested the hypothesis that DON interferes with the murine immune response to viral respiratory infection. Female Balb/c mice (5 weeks old) were orally gavaged with DON (10 mg/kg body weight [bw]) or saline vehicle and then intranasally instilled with 10(7) plaque-forming units of reovirus serotype 1, strain Lang (T1/L). At 10-day postinstillation (PI), both viral titers and reovirus L(2) gene expression were 10-fold higher in lungs of DON-treated mice than in saline controls. The lowest observed effective DON dose that impaired viral clearance was 2 mg/kg bw. Although DON amplified reovirus-induced interferon (IFN)-beta and IFN-gamma mRNA responses in lung, the toxin suppressed mRNA expression for IFN-alpha, IFN-alphabeta receptor (IFNAR), and IFN-gamma receptor (IFNGR). DON also impaired induction of two type 1 IFN-dependent antiviral genes, double-stranded RNA activated protein kinase R (PKR) and oligoadenylate synthase 2 (OAS2). Respiratory reovirus infection caused a mild bronchopneumonia in mice which was markedly exacerbated by DON as evidenced by severe inflammatory cell infiltration, marked alveolar damage, and a higher volume density of intraepithelial mucosubstances in pulmonary airways. At 3- and 7-day PI, elevations in total protein, MCP-1, TNF-alpha, total cells, macrophages, neutrophils, and lymphocytes were observed in bronchoalveolar lavage fluid (BALF) of control mice infected with reovirus. DON markedly enhanced viral-induced elevations of protein, MCP-1, TNF-alpha, and inflammatory cells in the BALF at 3-day PI. DON exposure also upregulated induction of reovirus-specific immunoglobulin A (IgA) in BALF, fecal pellets, and serum. DON's effect on BALF IgA was preceded by elevated IL-6 expression and secretion in the lung. Taken together, the results suggest that DON compromised resistance to respiratory viral infection. Reduced expression of IFNAR and type 1 IFN-mediated genes in the lung might contribute to DON impairment of pulmonary reovirus clearance, whereas exacerbation of bronchopneumonia and IgA responses corresponded to increased MCP-1, TNF-alpha, and IL-6 expression.
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PMID:Deoxynivalenol exacerbates viral bronchopneumonia induced by respiratory reovirus infection. 1709 Jun 20

Previous studies have indicated that lipopolysaccharide (LPS) from Gram-negative bacteria in plaque induces the release of prostaglandin E(2) (PGE(2)), which promotes alveolar bone resorption in periodontitis, and that tobacco smoking might be an important risk factor for the development and severity of periodontitis. We determined the effect of nicotine and LPS on alkaline phosphatase (ALPase) activity, PGE(2) production, and the expression of cyclooxygenase (COX-1, COX-2), PGE(2) receptors Ep1>4, and macrophage colony stimulating factor (M-CSF) in human osteoblastic Saos-2 cells. The cells were cultured with 10(-3) M nicotine in the presence of 0, 1, or 10 mug/ml LPS, or with LPS alone. ALPase activity decreased in cells cultured with nicotine or LPS alone, and decreased further in those cultured with both nicotine and LPS, whereas PGE(2) production significantly increased in the former and increased further in the latter. By itself, nicotine did not affect expression of COX-1, COX-2, any of the PGE(2) receptors, or M-CSF, but when both nicotine and LPS were present, expression of COX-2, Ep3, Ep4, and M-CSF increased significantly. Simultaneous addition of 10(-4) M indomethacin eliminated the effects of nicotine and LPS on ALPase activity, PGE(2) production, and M-CSF expression. Phosphorylation of protein kinase A was high in cells cultured with nicotine and LPS. These results suggest that LPS enhances the production of nicotine-induced PGE(2) by an increase in COX-2 expression in osteoblasts, that nicotine-LPS-induced PGE2 interacts with the osteoblast Ep4 receptor primarily in autocrine or paracrine mode, and that the nicotine-LPS-induced PGE(2) then decreases ALPase activity and increases M-CSF expression.
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PMID:Lipopolysaccharide enhances the production of nicotine-induced prostaglandin E2 by an increase in cyclooxygenase-2 expression in osteoblasts. 1734 54

Failure to control oxidative stress is closely related to aging and to a diverse range of human diseases. We have reported that protein kinase C gamma (PKCgamma) acts as a primary oxidative stress sensor in the lens. PKCgamma has a Zn-finger C1B stress switch domain, residues 101-150. Mutation, H101Y, in the C1B domain of PKCgamma proteins causes a failure of the PKCgamma oxidative stress response [Lin, D., Takemoto, D.J., 2005. Oxidative activation of protein kinase Cgamma through the C1 domain. Effects on gap junctions. J. Biol. Chem. 280, 13682-13693]. Some human neurodegenerative spinocerebellar ataxia type 14 are caused by mutations in the PKCgamma C1B domain. In the current study we have investigated the effects of these mutations on lens epithelial cell responses to oxidative stress. The results demonstrate that PKCgamma C1B mutants had lower basal enzyme activities and were not activated by H(2)O(2). Furthermore, the PKCgamma mutations caused a failure of endogenous wild type PKCgamma to be activated by H(2)O(2). These PKCgamma mutations abolished the effect of H(2)O(2) on phosphorylation of Cx43 and Cx50 by H(2)O(2) activation of PKCgamma. The cells with PKCgamma C1B mutations had more Cx43 and/or Cx50 gap junction plaques which were not decreased by H(2)O(2). Since open gap junctions could have a bystander effect this could cause apoptosis to occur. H(2)O(2) (100 microM, 3 h) activated a caspase-3 apoptotic pathway in the lens epithelial cells but was more severe in cells expressing PKCgamma mutations. The presence of 18alpha-glycyrrhetinic acid (AGA), an inhibitor of gap junctions, decreased Cx43 and Cx50 protein levels and gap junction plaque number. This reduction in gap junctions by AGA resulted in inhibition of H(2)O(2)-induced apoptosis. Our results demonstrate that there is a dominant negative effect of PKCgamma C1B mutations on endogenous PKCgamma which results in loss of control of gap junctions. Modeled structures suggest that the severity of C1B mutation effects may be related to the extent of loss of C1B structure. Mutations in the C1B domain of PKCgamma result in increased apoptosis in lens epithelial cells. This can be prevented by a gap junction inhibitor. Thus, propagation of apoptosis from cell-to-cell in lens epithelial cells may be through open gap junctions. The control of gap junctions requires PKCgamma.
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PMID:Protein kinase C gamma mutations in the C1B domain cause caspase-3-linked apoptosis in lens epithelial cells through gap junctions. 1749 14

Atherosclerosis is a chronic inflammatory disease and represents the major cause of cardiovascular morbidity and mortality. A critical regulator of inflammatory processes represents the mitogen-activated protein kinase-activated protein kinase-2 (MK2). Therefore, we investigated the functional role of MK2 in atherogenesis in hypercholesterolemic mice as well as potentially underlying mechanisms in vivo and in vitro. Activation of MK2 (phospho-MK2) was predominantly detected in the endothelium and macrophage-rich plaque areas within aortas of hypercholesterolemic LDL receptor-deficient mice (ldlr(-/-)). Systemic MK2 deficiency of hypercholesterolemic ldlr(-/-) mice (ldlr(-/-)/mk2(-/-)) significantly decreased the accumulation of lipids and macrophages in the aorta after feeding an atherogenic diet for 8 and 16 weeks despite a significant increase in proatherogenic plasma lipoproteins compared with ldlr(-/-) mice. Deficiency of MK2 significantly decreased oxLDL-induced foam cell formation in vitro, diet-induced foam cell formation in vivo, and expression of scavenger receptor A in primary macrophages. In addition, systemic MK2 deficiency of hypercholesterolemic ldlr(-/-) mice significantly decreased the aortic expression of the adhesion molecule VCAM-1 and the chemokine MCP-1, key mediators of macrophage recruitment into the vessel wall. Furthermore, silencing of MK2 in endothelial cells by siRNA reduced the IL-1beta-induced expression of VCAM-1 and MCP-1. MK2 critically promotes atherogenesis by fostering foam cell formation and recruitment of monocytes/macrophages into the vessel wall. Therefore, MK2 might represent an attractive novel target for the treatment of atherosclerotic cardiovascular disease.
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PMID:Systemic deficiency of the MAP kinase-activated protein kinase 2 reduces atherosclerosis in hypercholesterolemic mice. 1788 19

The cyclin-dependent kinase (CDK) inhibitor p16(INK4a) and the MDM2 ubiquitin ligase inhibitor p19(ARF) are critical to the regulation of cell cycle progression. Their loss by deletion, mutation or epigenetic silencing is a common molecular alteration in many human cancers. To investigate the role of p16(INK4a)/p19(ARF) deficiency in CNS tumor pathogenesis, pregnant mice bearing p16(-/-)/p19(-/-), p16(+/-)/p19(+/-), and p16(+/+)/p19(+/+) embryos were exposed transplacentally on gestation day 14 to a single dose of the potent carcinogen, ethylnitrosourea (ENU). p16(+/-)/p19(+/-) male mice treated with ENU developed meningial proliferative lesions with a high incidence (5/10). The incidence was lower in other ENU-treated animals of both sexes and none occurred in saline-treated control animals. The lesions ranged from widespread meningeal proliferation and plaque-like thickening by neoplastic spindle cells consistent with meningiomatosis to a larger discrete mass consistent with a meningioma. Ultrastructural analysis revealed the presence of intercellular junctions between cells, supporting a meningothelial histogenesis. Spontaneous meningiomas occur rarely in wild-type mice but are a common neoplasm afflicting humans, accounting for between 13 and 26% of primary intracranial neoplasms. This ENU inducible meningeal lesion in p16(+/-)/p19(+/-) mice may provide additional insight into the pathogenesis of meningeal neoplasia and aid the development of therapeutics.
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PMID:N-ethyl-N-nitrosourea (ENU)-induced meningiomatosis and meningioma in p16(INK4a)/p19(ARF) tumor suppressor gene-deficient mice. 1794 59

Beside their main physiological function in hemostasis, platelets are also highly involved in pathological processes, such as atherothrombosis and inflammation. During hemostasis, binding of adhesive substrates to tyrosine-kinase-linked adhesion receptors and/or soluble agonists to G-protein coupled receptors leads to a cascade of intracellular signaling processes based on substrate (de)phosphorylation. The same mechanisms are involved in platelet activation at sites of atherosclerotic plaque rupture, contributing to vessel occlusion and consequently to pathologic states, such as myocardial infarction, stroke, or peripheral artery disease. To gain a deeper insight into platelet function, we analyzed the phosphoproteome of resting platelets and identified 564 phosphorylation sites from more than 270 proteins, of which many have not been described in platelets before. Among those were several unknown potential protein kinase A (PKA) and protein kinase G (PKG) substrates. Because platelet inhibition is tightly regulated especially by PKA and PKG activity, these proteins may represent important new targets for cardiovascular research. Thus, our finding that GPIbalpha is phosphorylated at Ser603 in resting platelets may represent a novel mechanism for the regulation of one of the most important platelet receptor (GPIb-IX-V) mediated signaling pathways by PKA/PKG.
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PMID:Phosphoproteome of resting human platelets. 1808 87

Testis-specific protein kinases are important because of their potential role in spermiogenesis, sperm maturation, and sperm function. In the present study, a novel serine-threonine kinase with high identity to human serine-threonine kinase 31 (STK31) was cloned from equine testis and expression of the protein was characterized in equine testis and ejaculated spermatozoa. Five over-lapping independent clones were plaque purified after screening of a lambda ZAP cDNA expression library constructed from equine testis. Sequence analysis and alignment of all five clones showed high identity with human STK31 with approximately 200 bp of the equine N-terminal sequence incomplete. The putative full-length coding sequence of this testis specific equine cDNA was completed by amplification of a 200-bp fragment using a human primer upstream of the reported translational start site with equine specific nested primers. Northern blot analysis using the equine STK31 cDNA detected an RNA transcript of approximately 3.1 kb present in testis but not in other reproductive or somatic tissues. Immunolocalization of the protein in equine testis and spermatozoa demonstrated that STK31 was present in post-meiotic germ cells with localization to the equatorial segment of testicular spermatozoa. Analysis of the domain structure of equine STK31 revealed a protein kinase domain along with a putative RNA-binding region. The post-meiotic expression of this protein along with its domain structure suggests that STK31 may have a role in reorganization of sperm chromatin during spermiogenesis. The cloning of this novel, testis-specific equine STK provides a new tool to explore the role of kinases in sperm function.
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PMID:Characterization of a novel, testis-specific equine serine/threonine kinase. 1824 30

Recent studies showed correlation between increased serum apolipoprotein B-100 (apoB-100) level and Alzheimer's disease. To reveal the possible role of apoB-100 in neurodegeneration, we analyzed the serum lipoprotein and cerebral protein profiles, amyloid plaque formation, apoptosis and brain morphology of transgenic mice overexpressing the human apoB-100 protein. Serum lipoprotein profile showed significant increase of the plasma triglyceride level, while no alteration in total cholesterol was detected. The antibody microarray experiment revealed upregulation of several cytoskeletal, neuronal proteins and proteins that belong to the mitogen activated protein kinase pathway, indicating active apoptosis in the brain. Histochemical experiments showed formation of amyloid plaques and extensive neuronal death. Biochemical changes severely affected brain morphology; a dramatic genotype-dependent enlargement of the third and lateral ventricles in the brain was detected. On the basis of earlier and present results, we conclude that overexpressed human apoB-100 protein significantly increases the level of serum lipids (triglyceride upon normal chow diet and cholesterol on cholesterol-rich diet) which leads to cerebrovascular lesions and subsequently induces apoptosis and neurodegeneration.
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PMID:Overexpression of human apolipoprotein B-100 induces severe neurodegeneration in transgenic mice. 1847 52


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