Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by 2 genes, GSK3A and GSK3B. GSK-3 is thought to be involved in tissue repair and fibrogenesis, but its role in these processes is currently unknown. To investigate the function of GSK-3beta in fibroblasts, we generated mice harboring a fibroblast-specific deletion of Gsk3b and evaluated their wound-healing and fibrogenic responses. We have shown that Gsk3b-conditional-KO mice (Gsk3b-CKO mice) exhibited accelerated wound closure, increased fibrogenesis, and excessive scarring compared with control mice. In addition, Gsk3b-CKO mice showed elevated collagen production, decreased cell apoptosis, elevated levels of profibrotic alpha-SMA, and increased myofibroblast formation during wound healing. In cultured Gsk3b-CKO fibroblasts, adhesion, spreading, migration, and contraction were enhanced. Both Gsk3b-CKO mice and fibroblasts showed elevated expression and production of endothelin-1 (ET-1) compared with control mice and cells. Antagonizing ET-1 reversed the phenotype of Gsk3b-CKO fibroblasts and mice. Thus, GSK-3beta appears to control the progression of wound healing and fibrosis by modulating ET-1 levels. These results suggest that targeting the GSK-3beta pathway or ET-1 may be of benefit in controlling tissue repair and fibrogenic responses in vivo.
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PMID:GSK-3beta in mouse fibroblasts controls wound healing and fibrosis through an endothelin-1-dependent mechanism. 1904 45

Increased activation of poly(ADP-ribose) polymerase (PARP) enzyme has been implicated in the pathogenesis of acute and chronic myocardial dysfunction. We have demonstrated the protective effect of PARP inhibitors against postinfarction myocardial remodeling and heart failure. The primary aim of our recent work was to compare the effect and efficacy of a potent PARP-inhibitor (L-2286) to enalapril, a widely used angiotensin-converting enzyme (ACE) inhibitor. in experimental heart failure model. Both L-2286 and enalapril were tested in a rat model of chronic heart failure after isoproterenol-induced myocardial infarction. After a 12-week treatment period, echocardiography was performed, cardiac hypertrophy and interstitial collagen deposition were assessed, and the phosphorylation state of Akt-1/GSK-3beta pathway as well as the PKC and MAPK kinases were determined. Both PARP and ACE inhibition reduced the progression of postinfarction heart failure by attenuating cardiac hypertrophy and interstitial fibrosis. More importantly, PARP inhibition increased the activity of the prosurvival signal transduction factors (Akt-1/GSK-3beta pathway, PKCepsilon). Due to these effects, L-2286 improved the systolic left ventricular function. Enalapril treatment exerted a similar, but weaker protective effect against postinfarction myocardial remodeling and heart failure. In conclusion, we demonstrated in an experimental heart failure model that L-2286 decreased the postinfarction myocardial remodeling more effectively than enalapril treatment.
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PMID:Effect of L-2286, a poly(ADP-ribose)polymerase inhibitor and enalapril on myocardial remodeling and heart failure. 1880 6

The intestinal epithelium is repetitively deformed by shear, peristalsis, and villous motility. Such repetitive deformation stimulates the proliferation of intestinal epithelial cells on collagen or laminin substrates via ERK, but the upstream mediators of this effect are poorly understood. We hypothesized that the phosphatidylinositol 3-kinase (PI3K)/AKT cascade mediates this mitogenic effect. PI3K, AKT, and glycogen synthase kinase-3beta (GSK-3beta) were phosphorylated by 10 cycles/min strain at an average 10% deformation, and pharmacologic blockade of these molecules or reduction by small interfering RNA (siRNA) prevented the mitogenic effect of strain in Caco-2 or IEC-6 intestinal epithelial cells. Strain MAPK activation required PI3K but not AKT. AKT isoform-specific siRNA transfection demonstrated that AKT2 but not AKT1 is required for GSK-3beta phosphorylation and the strain mitogenic effect. Furthermore, overexpression of AKT1 or an AKT chimera including the PH domain and hinge region of AKT2 and the catalytic domain and C-tail of AKT1 prevented strain activation of GSK-3beta, but overexpression of AKT2 or a chimera including the PH domain and hinge region of AKT1 and the catalytic domain and C-tail of AKT2 did not. These data delineate a role for PI3K, AKT2, and GSK-3beta in the mitogenic effect of strain. PI3K is required for both ERK and AKT2 activation, whereas AKT2 is sequentially required for GSK-3beta. Furthermore, AKT2 specificity requires its catalytic domain and tail region. Manipulating this pathway may prevent mucosal atrophy and maintain the mucosal barrier in conditions such as ileus, sepsis, and prolonged fasting when peristalsis and villous motility are decreased and the mucosal barrier fails.
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PMID:Strain-induced proliferation requires the phosphatidylinositol 3-kinase/AKT/glycogen synthase kinase pathway. 1904 55

The anti-inflammatory peptide early pregnancy factor/chaperonin 10 (cpn10) was identified by 2D-electrophoresis/mass spectrometry as one of the proteins increased in human umbilical cord endothelial cells (HUVEC) after treatment with erythropoietin (EPO). EPO increased the amount of cpn10 released into the medium of HUVEC cultures, despite the absence of a secretory signal peptide. Although immunosupressive agents would represent an indirect advantage for red cell formation under conditions of infection and inflammation, it is possible that cpn10 may have direct effects on erythroid cells. We show that the chaperonin decreased cell proliferation in cultures of the erythroleukemia cell line K562 and increased the amounts of the erythroid differentiation markers glycophorin A and hemoglobin in TF-1 cells. Nevertheless, cpn10 is not a specific erythroid cell differentiation factor, because monolayers of skin fibroblasts overexpressing cpn10 had significantly higher levels of the differentiation marker collagen I than normal fibroblasts. Nothing is known about the mechanism of action of cpn10 in its capacity as a general differentiation factor. An analysis of early changes taking place in K562 cells after incubation with cpn10 using antibody microarrays identified several phosphorylation events, including a decrease of GSK-3alpha phosphorylation. Further studies in TF-1 cells indicated that cpn10 decreased the phosphorylation of cofilin-1 while stimulating that of GSK-3beta. Furthermore, glycophorin A production decreased in the presence of a GSK-3 inhibitor in the same cells. These experiments support the idea that GSK-3-regulated signal transduction pathways are not only important for stem cell maintenance but may be involved in events controlling cell differentiation.
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PMID:Chaperonin 10 as an endothelial-derived differentiation factor: role of glycogen synthase kinase-3. 1914 74

Recombinant human erythropoietin (rHuEPO), which has been used clinically for the management of renal anemia, is reported to exert pleiotropic beneficial properties against acute ischemic/reperfusion injury in various tissues. To investigate the hypothesis that chronic treatment with rHuEPO might ameliorate diabetic nephropathy beyond hematopoiesis, rHuEPO (150 U/kg, subcutaneously) was administered three times per week to the streptozotocin-induced diabetic rats for 4 weeks. Streptozotocin (65 mg/kg, intravenously) significantly increased urinary protein excretion and collagen deposition in glomerular and tubulointerstitial areas in the kidney, which were attenuated by rHuEPO. rHuEPO normalized the levels of creatinine clearance, serum creatinine, and blood urea nitrogen of diabetic rats. RT-PCR analysis revealed that the expressions of mRNA for transforming growth factor-beta, osteopontin and adhesion molecules were enhanced in the diabetic rat kidney and that the overexpression of these molecules was suppressed by rHuEPO. rHuEPO exerted antioxidant properties by inhibiting renal activation and overexpression of NADPH oxidase. We found the activation of the Akt signaling pathway by the increased expression of phosphorylated Akt and GSK-3beta and a reduction of TUNEL-positive apoptotic cell death in renal tissue from rHuEPO-treated diabetic group. We also demonstrated that rHuEPO restored the endothelial nitric oxide synthase (eNOS) content in the diabetic rat kidney. On the other hand, treatment with rHuEPO did not affect blood glucose level, blood pressure, or hematocrit in diabetic rats. These results suggest that chronic treatment with rHuEPO attenuated renal injury beyond hematopoiesis and regulated apoptosis and eNOS expression, which might be due to the activation of Akt pathway.
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PMID:Chronic treatment with recombinant human erythropoietin exerts renoprotective effects beyond hematopoiesis in streptozotocin-induced diabetic rat. 1935 35

Integrin-linked kinase (ILK) is an intracellular serine/threonine protein kinase that regulates cell adhesion, survival, and epithelial-to-mesenchymal transition (EMT). In this study, we investigated the kinase activity of ILK during tubular EMT induced by TGF-beta1 and examined the therapeutic potential of an ILK inhibitor in obstructive nephropathy. TGF-beta1 induced a biphasic activation of ILK in renal tubular epithelial cells, with rapid activation starting at 5 min and the second wave of activation peaking at 24 h; the latter paralleled the induction of ILK protein expression. Pharmacologic inhibition of ILK with small-molecule inhibitor QLT-0267 abolished TGF-beta1-induced phosphorylation of Akt and glycogen synthase kinase-3beta, suppressed cyclin D1 expression, and largely restored the expression of E-cadherin and zonula occludens 1. Inhibition of ILK also blocked TGF-beta1-mediated induction of fibronectin, Snail1, plasminogen activator inhibitor 1, and matrix metalloproteinase 2. In a mouse model of obstructive nephropathy, administration of QLT-0267 inhibited beta-catenin accumulation; suppressed Snail1, alpha-smooth muscle actin, fibronectin, vimentin, and type I and type III collagen expression; and reduced total tissue collagen content. Inhibition of ILK did not affect kidney structure or function in normal mice. These findings suggest that increased ILK activity mediates EMT and the progression of renal fibrosis. Pharmacologic inhibition of ILK signaling may hold therapeutic potential for fibrotic kidney diseases.
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PMID:Inhibition of integrin-linked kinase attenuates renal interstitial fibrosis. 1954 9

Diabetic cardiomyopathy is manifested by compromised systolic and diastolic function. This study was designed to examine the role of advanced glycation endproduct (AGE) and AGE receptor (RAGE) in diabetic cardiomyopathy. Heart function was assessed in isolated control and streptozotocin-induced diabetic hearts following in vivo RAGE gene knockdown using RNA interference. Cardiomyocyte mechanical properties were evaluated including peak shortening (PS), time-to-PS (TPS) and time-to-90% relengthening (TR(90)). RAGE was assayed by RT-PCR and immunoblot. Diabetes significantly enhanced cardiac MG, AGE and RAGE levels accompanied with colocalization of AGE and RAGE in cardiomyocytes. Diabetes-elicited increase in RAGE was inhibited by in vivo siRNA interference. The AGE formation inhibitor benfotiamine significantly attenuated diabetes-induced elevation in MG, AGE, RAGE and collagen cross-linking without affecting hypertriglyceridaemia and hypercholesterolaemia in diabetes. Diabetes markedly decreased LV contractility, as evidenced by reduced +/-dP/dt and LV developed pressure (LVDP), which were protected by RAGE gene knockdown. In addition, MG-derived AGE (MG-AGE) up-regulated cardiac RAGE mRNA and triggered cardiomyocyte contractile dysfunction reminiscent of diabetic cardiomyopathy. The MG-AGE-elicited prolongation of TPS and TR(90) was ablated by an anti-RAGE antibody in cardiomyocytes. Interestingly, MG-AGE-induced cardiomyocyte dysfunction was associated with mitochondrial membrane potential (MMP) depolarization and reduced GSK-3beta inactivation in control cardiomyocytes, similar to those from in vivo diabetes. Treatment with siRNA-RAGE ablated diabetes-induced MMP depolarization and GSK-3beta inactivation. Collectively, our result implicated a role of AGE-RAGE in the pathogenesis of diabetic cardiomyopathy.
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PMID:Advanced glycation endproduct (AGE) accumulation and AGE receptor (RAGE) up-regulation contribute to the onset of diabetic cardiomyopathy. 1960 45

Elevating intracellular cAMP has been shown to inhibit platelet function. cAMP interferes with platelet-activating signals which lead to aggregation inhibition, but the precise mechanism is unclear. The present study examined if cAMP-elevating agents inhibited phosphatidylinositol 3-kinase (PI3-kinase) signaling in rat platelets by immunoblotting. Akt is one of the key molecules downstream of PI3K, and is phosphorylated by collagen stimulation. The phosphodiesterase-3 (PDE3) inhibitors cilostamide and cilostazol, and the adenylate cyclase activator forskolin, inhibited collagen-induced Akt phosphorylation at Ser473. The inhibitory effects of these cAMP-elevating agents on Akt phosphorylation were unchanged in the presence of the PKA (cyclic AMP-dependent protein kinase) inhibitor H-89. These effects were consistent with inhibition of platelet aggregation. It is known that inhibition of Akt phosphorylation leads to inhibition of phosphorylation of glycogen synthase kinase 3-beta (GSK-3beta), which is an effector of Akt, but cAMP-elevating agents stimulated GSK-3beta phosphorylation at Ser9. The PKA inhibitor H-89 attenuated GSK-3beta phosphorylation. The cAMP-elevating agents cilostamide, cilostazol and forskolin did not directly affect the enzyme activity of PI3-kinase. These results suggested that cAMP-elevating agents have two effects on PI3K signalling: inhibition of Akt phosphorylation independent of PKA; and stimulation of GSK-3beta phosphorylation dependent on PKA. Our results provide new insights into the inhibitory effect of cAMP-elevating agents on platelet function.
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PMID:Effects of the cAMP-elevating agents cilostamide, cilostazol and forskolin on the phosphorylation of Akt and GSK-3beta in platelets. 1965 84

Rho family protein regulates variety of cellular functions as cytoskeletal organization, cell proliferation and apoptosis. In the present study, we demonstrate that RhoB-overexpressed prostate cancer cells showed an enhanced cell motility and the administration of the GSK-3 inhibitors inhibited this increase in migration. Among the extracellular matrix and adhesion-related molecules, MMP1 RNA expression was increased in RhoB-overexpressed cells, administration of MMP inhibitor suppressed the collagen gel invasion in these cells. This is the first report evaluating RhoB function and the downstream signaling events in prostate cancer cell. Our results indicate that RhoB promotes cell motility and invasion in a metastatic prostate cancer cell.
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PMID:RhoB enhances migration and MMP1 expression of prostate cancer DU145. 1978 69

The vasoactive peptide urotensin-II (U-II) is likely to play a key causal role in cardiac remodeling that ultimately leads to heart failure. Its contribution, specifically to the development of diastolic dysfunction and the downstream intracellular signaling, however, remains unresolved. This study interrogates the effect of chronic U-II infusion in normal rats on cardiac structure and function. The contribution of Rho kinase (ROCK) signaling to these pathophysiological changes is evaluated in cell culture studies. Chronic high-dose U-II infusion over 4 wk significantly impaired diastolic function in rats on echocardiography-derived Doppler indexes, including E-wave deceleration time (vehicle 56.7 +/- 3.3 ms, U-II 118.0 +/- 21.5 ms; P < 0.01) and mitral valve annulus peak early/late diastolic tissue velocity (vehicle 2.01 +/- 0.19 ms, U-II 1.04 +/- 0.25 ms; P < 0.01). A lower dose of U-II infusion (1 nmol.kg(-1).h(-1)) yielded comparable changes. Diastolic dysfunction was accompanied by molecular [significant increases in procollagen-alpha(1)(I) gene expression on real-time PCR] and morphological (increases in total collagen, P < 0.05, and collagen type-I protein deposition, P < 0.001) evidence of left ventricular (LV) fibrosis following high-dose U-II infusion. The ROCK inhibitor GSK-576371 (10(-7) to 10(-5) M) elicited concentration-dependent inhibition of U-II (10(-7) M)-stimulated cardiac fibroblast collagen synthesis and cardiac myocyte protein synthesis. Chronic U-II infusion causes diastolic dysfunction, caused by fibrosis of the LV. The in vitro data suggest that this may be in part occurring via a ROCK-dependent pathway.
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PMID:Chronic urotensin-II infusion induces diastolic dysfunction and enhances collagen production in rats. 2000 68


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