Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P67775 (alpha isoform)
 797 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in the expression and activation of protein kinase C (PKC) have been implicated in the pathogenesis of diabetic neuropathy. Recent studies in liver, retina, and cardiovascular tissues from experimentally diabetic rats have demonstrated that diabetes has a selective effect on the expression and subcellular distribution of isozymes of PKC. In the light of this evidence, we investigated the expression of the PKC isozymes alpha, betaI, betaII, and gamma in sciatic nerves, spinal cords, and in the L4,5 dorsal root ganglia from streptozotocin-induced diabetic rats. Six weeks of diabetes had differential effects on the expression and distribution of PKC isozymes in sciatic nerves and spinal cords. In the sciatic nerves there was an apparent translocation of the alpha isoform from the cytosolic to the particulate fractions, the betaII isoform was reduced in the cytosolic fraction, and the betaI and gamma isoforms were unaffected. The changes in the isozyme immunoreactivities in the nerves were not a direct result of changes in either spinal cord or dorsal root ganglia alone, suggesting that diabetes has different effects on motor and sensory fibres and/or on Schwann cells. In nerves that had been crushed 14 days previously there was an increase in total PKC alpha immunoreactivity. This increase was potentiated in diabetic rats. On the other hand, PKC betaII immunoreactivity in crushed nerves was unaffected by diabetes. The data are consistent with diabetes-induced changes in expression of PKC betaII contributing to nerve damage, and changes in PKC alpha being a consequence of it.
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PMID:Protein kinase C isozyme expression in sciatic nerves and spinal cords of experimentally diabetic rats. 913 70

Induction of protein kinase C (PKC) pathway in the vascular tissues by hyperglycemia has been associated with many of the cellular changes observed in the complications of diabetes. Recently, we have reported that the use of a novel, orally effective specific inhibitor of PKC beta isoform (LY333531) normalized many of the early retinal and renal hemodynamics in rat models of diabetes. In the present study, we have characterized a spectrum of biochemical and molecular abnormalities associated with chronic changes induced by glucose or diabetes in the cultured mesangial cells and renal glomeruli that can be prevented by LY333531. Hyperglycemia increased diacylglycerol (DAG) level in cultured mesangial cells exposed to high concentrations of glucose and activated PKC alpha and beta1 isoforms in the renal glomeruli of diabetic rats. The addition of PKC beta selective inhibitor (LY333531) to cultured mesangial cells inhibited activated PKC activities by high glucose without lowering DAG levels and LY333531 given orally in diabetic rats specifically inhibited the activation of PKC beta1 isoform without decreasing PKC alpha isoform activation. Glucose-induced increases in arachidonic acid release, prostaglandin E2 production, and inhibition of Na+-K+ ATPase activities in the cultured mesangial cells were completely prevented by the addition of LY333531. Oral feeding of LY333531 prevented the increased mRNA expression of TGF-beta1 and extracellular matrix components such as fibronectin and alpha1(IV) collagen in the glomeruli of diabetic rats in parallel with inhibition of glomerular PKC activity. These results suggest that the activation of PKC, predominately the beta isoform by hyperglycemia in the mesangial cells and glomeruli can partly contribute to early renal dysfunctions by alteration of prostaglandin production and Na+-K+ ATPase activity as well as the chronic pathological changes by the overexpression of TGF-beta1 and extracellular matrix components genes.
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PMID:Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. 920 63

There is evidence that mediators of inflammation including components of the cytokine system are present in human and experimental diabetic kidney disease. CCAAT/enhancer-binding proteins (C/EBPs) represent a family of cytokine-inducible transcription factors. C/EBPs themselves regulate cytokine expression and also the expression of acute-phase reactants and connective tissue proteins. At least three C/EBP isoforms (alpha, beta, delta) are known. Upon stimulation with cytokines or bacterial lipopolysaccharide, the expression of the alpha isoform typically decreases, and the expression of the beta and/or delta isoforms increases. In view of the fact that components of the inflammatory response are present in diabetic kidney disease, there is a potential that the expression and activity of renal C/EBPs are altered in the diabetic state. In this study we sought to examine the status of C/EBP proteins in kidneys of rats with streptozotocin-induced diabetes mellitus. Diabetes was induced in 5 male Sprague-Dawley rats. Eight weight-matched non-diabetic rats were used as controls. Animals were sacrificed after 4 weeks, and the whole kidney nuclear protein was extracted. An electrophoretic mobility shift assay showed that DNA-binding activity was present in all five kidney nuclear extracts of the diabetic animals, but in only 2 out of 8 control samples (p < 0.05). A supershift assay showed that the DNA-bound protein complex consisted mainly of the C/EBPbeta isoform. Western analysis showed an increase of the C/EBPbeta protein in renal nuclear extracts of the diabetic animals compared to controls (p < 0.05). There was a decrease of the C/EBPalpha protein in the kidney nuclear extracts of the diabetic animals compared to controls (p < 0.05). We conclude that renal C/EBP dynamics are altered in experimental diabetes mellitus and that the patterns of C/EBP changes resemble those observed after cytokine or lipopolysaccharide stimulation.
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PMID:Renal CCAAT/enhancer-binding proteins in experimental diabetes mellitus. 967 32

Activation of protein kinase C (PKC) by hyperglycemia is implicated in the pathogenesis of long-term diabetic complications. Monocyte activation and transformation into macrophages is a key step in the atherosclerotic process. Therefore, in this study, we sought to determine 1) the effect of hyperglycemia on monocyte PKC activity and on the distribution of Ca2+-dependent and diacylglycerol-sensitive PKC isoforms; and 2) whether the effects on these parameters are determined by hyperglycemia per se, independent of the diabetic state. The studies were performed in 19 type 2 diabetic patients and 14 control subjects. Plasma glucose concentration was higher and insulin sensitivity lower (both P < 0.01) in diabetic patients than in control subjects. Monocytes from diabetic patients showed similar cytosol PKC activity to those from control subjects but higher membrane PKC activity (78+/-6 vs. 50+/-5 pmol x min(-1) x mg(-1) protein; P < 0.01). A direct correlation was observed between fasting plasma glucose and membrane PKC activity (r2 = 0.4008, P = 0.0001). In contrast, a reciprocal correlation was observed between membrane PKC activity and insulin sensitivity index (r2 = 0.28, P < 0.05). Using immunoblotting analysis, we found that membrane beta2, but not alpha, isoform of PKC was more abundant in monocytes from diabetic patients. In diabetic patients, when euglycemia was acutely induced, membrane PKC activity decreased by approximately 42% and beta2 isoform by approximately 15%. In two normal subjects in whom hyperglycemia was induced, membrane PKC increased from 63 and 57 to 92 and 128.6 pmol x min(-1) x mg(-1) protein, respectively. This increase was associated with an increase in the membrane isoform beta2; alpha isoform was unchanged. We conclude that 1) monocytes express the glucose-sensitive beta2 isoform of PKC; 2) the prevailing plasma glucose acutely regulates the activity of the membrane PKC and the content of membrane PKC beta2 isoform; and 3) this effect appears to be a direct effect of glucose per se, since the phenomenon was observed in normal control subjects when hyperglycemia was induced. Monocyte PKC activation may account for the accelerated atherosclerosis of patients with type 2 diabetes.
Diabetes 1999 Jun
PMID:Protein kinase C activity is acutely regulated by plasma glucose concentration in human monocytes in vivo. 1034 22

We have previously shown that unsaturated fatty acids amplify platelet-derived-growth-factor (PDGF)-induced protein kinase C (PKC) activation in vascular smooth-muscle cells (VSMCs). Diacylglycerol-induced PKC activation is normally terminated by diacylglycerol kinases (DGKs). We thus hypothesized that fatty acids act by inhibiting a DGK. Fractionation of VSMC extracts demonstrated that the DGK alpha isoform was the major DGK activity present. PDGF markedly increased the DGK activity of cultured cells. An inhibitor selective for the DGK alpha isoform, R59949 [3-[2-[4-(bis-(4-fluorophenyl)methylene]piperidin-1-yl)ethyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone], abolished the growth-factor-induced increase in DGK activity, but had little effect on basal activity. PDGF thus selectively activates DGKalpha. Epidermal growth factor and alpha-thrombin stimulated total DGK activity similarly to PDGF. Activation by epidermal growth factor was sensitive to R59949, again suggesting involvement of DGKalpha. However, the alpha-thrombin-induced activity was unaffected by this agent. Unsaturated fatty acids inhibited growth-factor-induced DGKalpha activation, but had no effect on basal activity. Fatty acids also amplified the PDGF-induced increase in cell diacylglycerol content. These results indicate that inhibition of DGKalpha contributes to fatty-acid-induced amplification of PKC activation. Increased levels of fatty acids in diabetes may thus contribute to chronic PKC activation associated with this disorder.
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PMID:Fatty acids inhibit growth-factor-induced diacylglycerol kinase alpha activation in vascular smooth-muscle cells. 1141 60

Peroxisome proliferator-activated receptors (PPAR) are a family of nuclear receptors that regulate lipid and carbohydrate metabolism in response to extracellular fatty acids and their metabolites. They are crucial in the regulation of fat storage, besides having a potential role in insulin resistance syndrome. They have clinical relevance in understanding the cause and in development of drugs in common clinical conditions such as type 2 diabetes mellitus, cellular growth and neoplasia. Three types of receptors were identified: PPAR alpha, gamma and delta. Fibrate group of lipid lowering agents bind to the alpha isoform and glitazone group of insulin sensitizers to gamma isoform. Further advances can result in new drugs for atherosclerosis, malignancies and diabetes mellitus.
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PMID:Peroxisome proliferator-activated receptors as molecular targets for drug therapy. 1269 55

The insulin-responsive glucose transporter GLUT4 plays a crucial role in insulin-mediated facilitated glucose uptake into adipose tissue and muscle, and impaired expression of GLUT4 has been linked to obesity and diabetes. In this study, we demonstrate that liver X receptors (LXRs) regulate the expression of GLUT4 through direct interaction with a conserved LXR response element in the GLUT4 promoter. The expression of GLUT4 in WAT is induced by a potent LXR agonist in wild type, LXR alpha-/-, and LXR beta-/- mice but not in LXR alpha-/-beta-/- mice, demonstrating that both LXRs are able to mediate ligand activated transcription of the GLUT4 gene. However, basal and insulin stimulated expression of GLUT4 in epididymal WAT is reduced only in mice carrying ablation of the LXR alpha isoform. The expression of GLUT4 is furthermore correlated to the induction of LXR alpha during mouse and human adipocyte differentiation. LXR beta is thus apparently not able to rescue basal expression of GLUT4 in the absence of LXR alpha. We have previously demonstrated that LXR alpha is down-regulated in animal models of obesity and diabetes, thus revealing a striking correlation between GLUT4 and LXR alpha expression in insulin-resistant conditions. This suggests that the LXR alpha isoform has a unique role in adipose expression of GLUT4 and suggests that alteration of adipose tissue expression of LXR alpha might be a novel tool to normalize the expression of a gene that is dysregulated in diabetic and insulin-resistant conditions.
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PMID:Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor alpha. 1297 Mar 62

Calcineurin is an important signaling molecule in mesangial cells in vitro and is involved in some manifestations of diabetic nephropathy in vivo. However, calcineurin acts in a cell-specific and tissue-specific manner in the kidney, and mechanisms of specificity are unknown. Three closely related isoforms of the calcineurin A (CnA) subunit are expressed in a tissue-specific manner. This study was undertaken to determine if specificity of calcineurin action is linked to regulation of CnA isoforms in the diabetic kidney. After induction of diabetes with streptozotocin, expression of all three CnA isoforms rapidly increased, primarily in the thick ascending limb of Henle (TAL). After prolonged diabetes, increase specifically of the alpha isoform was observed in collecting ducts (CD) and in endothelial cells of glomeruli. Aquaporin 2 (AQP2), a putative substrate of calcineurin phosphatase in the kidney, is also involved in diabetic nephropathy. Co-localization of CnA isoforms with AQP2 revealed that CnA-alpha is the predominant isoform that associates with AQP2 in the diabetic kidney. Furthermore, inhibition of calcineurin with cyclosporin A (CsA) alters AQP2 localization and phosphorylation in principal cells of CD. Alterations in subcellular localization of AQP2 were parallel with CnA-alpha. Similarly, CsA treatment results in a further increase in urine output compared with diabetes alone, suggesting a functional consequence of inhibiting calcineurin-mediated regulation of AQP2. In conclusion, all three isoforms of CnA are upregulated in the diabetic kidney. Increased expression of CnA-alpha, in particular, is observed in glomeruli and CD and participates in regulation of AQP2 expression, phosphorylation, and function.
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PMID:Differential expression of calcineurin A isoforms in the diabetic kidney. 1515 53

Glycogen synthase kinase-3, a serine/threonine kinase, has been implicated in a wide variety of pathological conditions such as diabetes, Alzheimer's disease, stroke, bipolar disorder, malaria and cancer. Herein we report 3D-QSAR analyses using CoMFA and CoMSIA and molecular docking studies on 3-anilino-4-phenylmaleimides as GSK-3alpha inhibitors, in order to better understand the mechanism of action and structure-activity relationship of these compounds. Comparison of the active site residues of GSK-3alpha and GSK-3beta isoforms shows that all the key amino acids involved in polar interactions with the maleimides for the beta isoform are the same in the alpha isoform, except that Asp133 in the beta isoform is replaced by Glu196 in the alpha isoform. We prepared a homology model for GSK-3alpha, and showed that the change from Asp to Glu should not affect maleimide binding significantly. Docking studies revealed the binding poses of three subclasses of these ligands, namely anilino, N-methylanilino and indoline derivatives, within the active site of the beta isoform, and helped to explain the difference in their inhibitory activity.
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PMID:Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking. 1883 67

Cluster analysis of DNA microarray data that uses statistical algorithms to arrange the genes according to similarity in patterns of gene expression and the output displayed graphically is described in this article. Hierarchical clustering is a multivariate tool often used in phylogenetics, comparative genomics to relate the evolution of species. The patterns seen in microarray expression data can be interpreted as indications of the status of the genes responsible for nephropathy in peripheral blow cells of type 2 diabetes (T2DN). Out of 415 genes totally expressed in the 3 DNA chips it was concluded that only 116 genes expressed in T2DN and in that only 50 are functional genes. These 50 functional genes are responsible for diabetic nephropathy; of these 50, some of the genes which are more expressed and responsible are AGXT: Alanine-glyoxylate aminotransferase, RHOD: Ras homolog gene family, CAPN6: Calpain 6, EFNB2: Ephrin-B2, ANXA7: Annexin A7, PEG10: Paternally expressed 10, DPP4: Dipeptidyl-peptidase 4 (CD26, adenosine deaminase complexing protein 2), ENSA: Endosulfine alpha, IGFBP2: Insulin-like growth factor binding protein 2, 36kDa, CENPB: Centromere protein B, 80kDa, MLL3: Myeloid/lymphoid or mixed-lineage leukemia 3, BDNF: Brain-derived neurotrophic factor, EIF4A2: Eukaryotic translation initiation factor 4A, isoform 2, PPP2R1A: Protein phosphatase 2 (formerly 2A), regulatory subunit A, alpha isoform. Fifty genes and their nucleotide sequences are taken from NCBI and a phylogenetic tree is constructed using CLUSTAL W and the distances are closer to each other concluding that based on the sequence similarity and evolution the genes are expressed similarly. Literature survey is done for each gene in OMIM and the genes responsible for diabetic nephropathy are listed.
Int J Diabetes Dev Ctries 2010 Jan
PMID:Cluster analysis and phylogenetic relationship in biomarker identification of type 2 diabetes and nephropathy. 2043 8


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