Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ubiquitin-proteasome pathway plays a crucial role in the regulation of many physiological processes and in the development of a number of major human diseases, such as cancer, Alzheimer's, Parkinson's, diabetes, etc. As a new target, the study on the proteasome inhibitors has received much attention recently. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using comparative molecule field analysis (CoMFA) and comparative molecule similarity indices analysis (CoMSIA) techniques were applied to analyze the binding affinity of a set of tripeptide aldehyde inhibitors of 20S proteasome. The optimal CoMFA and CoMSIA models obtained for the training set were all statistically significant with cross-validated coefficients (q(2)) of 0.615, 0.591 and conventional coefficients (r(2)) of 0.901, 0.894, respectively. These models were validated by a test set of eight molecules that were not included in the training set. The predicted correlation coefficients (r(2)) of CoMFA and CoMSIA are 0.944 and 0.861, respectively. The CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of beta5 subunit of 20S proteasome, which suggests that the 3D-QSAR models built in this paper can be used to guide the development of novel inhibitors of 20S proteasome.
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PMID:3D-QSAR studies on tripeptide aldehyde inhibitors of proteasome using CoMFA and CoMSIA methods. 1625 51

Exposure to arsenic (As) is a risk factor for the development of diabetes, vascular diseases and cancer. Several theories have been proposed to account for the mechanisms potentially responsible for As toxicity and carcinogenesis. Currently, we have investigated whether the eukaryotic translation initiation factor 4E (eIF4E), the mRNA cap binding and rate limiting factor required for translation, is a target for As-induced cytotoxicity and cell death. We have also investigated the potential cellular mechanisms underlying the As-induced de-regulation of expression of eIF4E that are most likely responsible for the cytotoxicity and cell death induced by As. Exposure of four different human cell lines - HCT15 (colorectal adenocarcinoma), PLC/PR/5 (hepatocellular carcinoma), HeLa (cervical adenocarcinoma) and Chang (likely derived from HeLa cells) to sodium arsenite (NaAsO2) for time intervals up to 24 h resulted in a concentration-dependent cytotoxicity and cell death. All the NaAsO2-treated cells exhibited significant inhibition of eIF4E gene (protein). The potential involvement of eIF4E gene expression in the NaAsO2-induced cytotoxicity and cell death was investigated by silencing the cellular expression of the eIF4E gene by employing a small interfering RNA (SiRNA) specifically targeting the eIF4E gene's expression. The SiRNA-mediated silencing of eIF4E gene expression also resulted in significant cytotoxicity and cell death suggesting that the toxicity noticed among the NaAsO2-treated cells was probably due to the chemically induced inhibition of eIF4E gene expression. The potential involvement of inhibition of eIF4E gene expression in the NaAsO2-induced cytotoxicity and cell death was further investigated by employing transgenic cell lines overexpressing the eIF4E gene. Overexpression of the eIF4E gene in the Chinese hamster ovary cell line was protective against the NaAsO2-induced cytotoxicity and cell death. Additional studies conducted to understand the potential mechanisms responsible for NaAsO2-induced inhibition of eIF4E gene expression demonstrated that exposure to NaAsO2 resulted in transcriptional down-regulation of the eIF4E gene only in HCT-15 and HeLa cells, while in the NaAsO2-treated and PLC/PR/5 and Chang cells, the eIF4E mRNA expression level was comparable to those of the corresponding control cells. Cellular levels of ubiquitin and the process of ubiquitination were significantly higher in the NaAsO2-treated cells compared with the control cells. Immunoprecipitation of lysates obtained from the NaAsO2-treated cells and the subsequent western blot analysis of the immunoprecipitated protein(s) using the eIF4E antibody detected the presence of eIF4E protein in the immunoprecipitate suggesting possible ubiquitination of eIF4E protein in the NaAsO2-treated cells. Pre-exposure of the NaAsO2-treated cells to proteasome inhibitors blocked the inhibition of eIF4E gene expression as well as the resulting cytotoxicity and cell death. Furthermore, exposure of cells to NaAsO2 resulted in a significant inhibition of expression of the cell cycle and growth regulating gene, cyclin D1. Whether or not the inhibition of cyclin D1 in the NaAsO2-treated cells is mediated through the inhibition of eIF4E was tested by silencing the expression of eIF4E gene in the cells. Transfection of cells with SiRNA specifically targeting eIF4E gene expression resulted in a significant inhibition of cyclin D1 gene suggesting that the observed inhibition of cyclin D1 gene in the NaAsO2-treated cells is most likely mediated through inhibition of eIF4E gene. Taken together, our results indicate that the exposure of cells to NaAsO2 resulted in cytotoxicity and cell death, at least in part, due to the inhibition of eIF4E gene expression leading to diminished cellular levels of critical genes such as cyclin D1.
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PMID:Sodium arsenite-induced inhibition of eukaryotic translation initiation factor 4E (eIF4E) results in cytotoxicity and cell death. 1628 21

Recent mining of the human and mouse genomes, use of yeast genetics, and detailed analyses of several biochemical pathways, have resulted in the identification of many new roles for ubiquitin-proteasome mediated degradation of proteins. In the context of last year's award of Noble Prize (Chemistry) work, the ubiquitin and ubiquitin-like modifications are increasingly recognized as key regulatory events in health and disease. Although the ATP-dependent ubiquitin-proteasome system has evolved as premier cellular proteolytic machinery, dysregulation of this system by several different mechanisms leads to inappropriate degradation of specific proteins and pathological consequences. While aberrations in the ubiquitin-proteasome pathway have been implicated in certain malignancies and neurodegenerative disorders, recent studies indicate a role for this system in the pathogenesis of diabetes and its complications. Inappropriate degradation of insulin signaling molecules such as insulin receptor substrates (IRS-1 and IRS-2) has been demonstrated in experimental diabetes, mediated in part through the up-regulation of suppressors of cytokine signaling (SOCS). It appears that altered ubiquitin-proteasome system might be one of the molecular mechanisms of insulin resistance in many pathological situations. Drugs that modulate the SOCS action and/or proteasomal degradation of proteins could become novel agents for the treatment of insulin resistance and Type 2 diabetes.
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PMID:Is insulin signaling molecules misguided in diabetes for ubiquitin-proteasome mediated degradation? 1633 91

The transcription factor IPF1/PDX1 plays a crucial role in both pancreas development and maintenance of beta-cell function. Targeted disruption of this transcription factor in beta-cells leads to diabetes, whereas reduced expression levels affect insulin expression and secretion. Therefore, it is essential to determine molecular mechanisms underlying the regulation of this key transcription factor on mRNA levels and, most importantly, on protein levels. Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity. Oxidative stress, which is associated with the diabetic state, (i) increases IPF1/PDX1 Ser61 and/or Ser66 phosphorylation and (ii) increases the degradation rate and decreases the half-life of IPF-1/PDX-1 protein. In addition, we provide evidence that GSK3 activity participates in oxidative stress-induced effects on beta-cells. Thus, this current study uncovers a new mechanism that might contribute to diminished levels of IPF1/PDX1 protein and beta-cell dysfunction during the progression of diabetes.
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PMID:Phosphorylation marks IPF1/PDX1 protein for degradation by glycogen synthase kinase 3-dependent mechanisms. 1640 9

Abnormal accumulation of methylglyoxal, a physiological glucose metabolite, is considered a potential link between hyperglycemia and diabetes complications. Evidence has shown that methylglyoxal modifies cellular proteins by glycation and oxidation, resulting in dysfunction or loss of cellular proteins. Raf-1 protein-serine/threonine kinase serves as a central switch board in the transmission of many growth and developmental signals. It was reported that Raf-1 levels appear to decrease in some diabetic subjects. But the potential mechanisms have not yet been clarified. Here, we tested the hypothesis that methylglyoxal-mediated proteolysis might contribute to the downregulation of Raf-1 levels. We observed that a rapid and detectable decrease in Raf-1 protein levels was induced by methylglyoxal, which was accelerated by treating with a Raf-1 activator, phorbol-12-myristate-13-acetate, and by expressing active forms of Raf-1 and Ras. Moreover, immunoprecipitation and immunoblotting assays showed that co-treatment of cells with methylglyoxal and phorbol-12-myristate-13-acetate caused dramatic ubiquitination in both total intracellular proteins and Raf-1. Blocking phosphorylation with the protein kinase C inhibitor bisindolylmaleimide, or inhibiting intracellular oxidation by addition of the antioxidant N-acetyl-l-cysteine could reverse the ubiquitination and downregulation of Raf-1 induced by methylglyoxal and phorbol-12-myristate-13-acetate. These results suggest that methylglyoxal-mediated intracellular oxidation and ubiquitin/proteasome-dependent proteolysis are involved in the downregulation of Raf-1, which may be closely related to the development complications in diabetes.
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PMID:Methylglyoxal downregulates Raf-1 protein through a ubiquitination-mediated mechanism. 1650 66

The role of ubiquitin-proteasome system in the accelerated atherosclerotic progression of diabetic patients is unclear. We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic diabetic and nondiabetic patients, as well as the effect of rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma activator, in diabetic plaques. Plaques were obtained from 46 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Diabetic patients received 8 mg rosiglitazone (n = 23) or placebo (n = 23) for 4 months before scheduled endarterectomy. Plaques were analyzed for macrophages (CD68), T-cells (CD3), inflammatory cells (HLA-DR), ubiquitin, proteasome 20S activity, nuclear factor (NF)-kappaB, inhibitor of kappaB (IkappaB)-beta, tumor necrosis factor (TNF)-alpha, nitrotyrosine, matrix metalloproteinase (MMP)-9, and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay). Compared with nondiabetic plaques, diabetic plaques had more macrophages, T-cells, and HLA-DR+ cells (P < 0.001); more ubiquitin, proteasome 20S activity (TNF-alpha), and NF-kappaB (P < 0.001); and more markers of oxidative stress (nitrotyrosine and O2(-) production) and MMP-9 (P < 0.01), along with a lesser collagen content and IkappaB-beta levels (P < 0.001). Compared with placebo-treated plaques, rosiglitazone-treated diabetic plaques presented less inflammatory cells (P < 0.01); less ubiquitin, proteasome 20S, TNF-alpha, and NF-kappaB (P < 0.01); less nitrotyrosine and superoxide anion production (P < 0.01); and greater collagen content (P < 0.01), indicating a more stable plaque phenotype. Similar findings were obtained in circulating monocytes obtained from the two groups of diabetic patients and cultured in the presence or absence of rosiglitazone (7.0 micromol/l). Ubiquitin-proteasome over-activity is associated with enhanced inflammatory reaction and NF-kappaB expression in diabetic plaques. The inhibition of ubiquitin-proteasome activity in atherosclerotic lesions of diabetic patients by rosiglitazone is associated with morphological and compositional characteristics of a potential stable plaque phenotype, possibly by downregulating NF-kappaB-mediated inflammatory pathways.
Diabetes 2006 Mar
PMID:The ubiquitin-proteasome system and inflammatory activity in diabetic atherosclerotic plaques: effects of rosiglitazone treatment. 1650 24

Glycated protein products are formed upon binding of sugars to lysine and arginine residues and have been shown to accumulate during aging and in pathologies such as Alzheimer disease and diabetes. Often these glycated proteins are transformed into advanced glycation end products (AGEs) by a series of intramolecular rearrangements. In the study presented here we tested the ability of microglial cells to degrade BSA-AGE formed by glycation reactions of bovine serum albumin (BSA) with glucose and fructose. Microglial cells are able to degrade BSA-AGEs to a certain degree by proteasomal and lysosomal pathways. However, the proteasome and lysosomal proteases are severely inhibited by cross-linked BSA-AGEs. BSA-AGEs are furthermore able to activate microglial cells. This activation is accompanied by an enhanced degradation of BSA-AGE. Therefore, we conclude that microglial cells are able to degrade glycated proteins, although cross-linked protein-AGEs have an inhibitory effect on proteolytic systems in microglial cells.
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PMID:Degradation of glycated bovine serum albumin in microglial cells. 1654 Mar 97

The ubiquitin-proteasome pathway is crucial for protein turnover. Part of the pathway involves deubiquitination, which is carried out by cystein proteases known as ubiquitin COOH-terminal hydrolases. The isoform Uch-L1 was found to be present in large amounts in rat islets by immunostaining, Western blot analysis, and RT-PCR. Culturing islets in high glucose concentrations (16.7 mmol/l) for 24 h led to decreased gene expression. Exposure to chronic hyperglycemia following 90% partial pancreatectomy also led to reduced Uch-L1 expression. Expression of other members of the ubiquitin-proteasome pathway studied after culturing islets at high glucose concentrations revealed little change except for modest declines in parkin, human ubiquitin-conjugating enzyme 5 (UbcH5), and beta-TRCP (transducin repeat-containing protein). With the pancreatectomy model, expression of polyubiquitin-B and c-Cbl were increased and E6-associated protein was reduced. Further insight about the proteasome pathway was obtained with the proteasome inhibitor lactacystin, which in short-term 2-h experiments enhanced glucose-induced insulin secretion. An important role for the ubiquitin-proteasome pathways in beta-cells is suggested by the findings that changes in glucose concentration influence expression of genes in the pathway and that blockade of the proteasome degradation machinery enhances glucose-stimulated insulin secretion.
Diabetes 2006 May
PMID:Evidence for a role of the ubiquitin-proteasome pathway in pancreatic islets. 1664 76

Atrogin-1/MAFbx/FBXO32 is a muscle-specific ubiquitin-ligase (E3) that is dramatically increased in atrophying muscle. Here, we have investigated the functional relationship between atrogin-1 and FBXO25 which shares 65% amino acid identity. Using a RT-PCR, we demonstrated that FBXO25 is highly expressed in brain, kidney, and intestine, whereas atrogin-1 expression is largely restricted to striate muscle. FBXO25 was shown here to contain a functional F-box domain that binds to Skp1 and thereby to Roc1 and Cul1, the major components of SCF-type E3s. In addition, the productive SCF complex containing FBXO25 showed ubiquitin ligase activity. We investigated the differential expression of atrogin-1 and FBXO25 in fasted and dexamethasone-treated mice and also in rats with streptozotocin-induced diabetes. Although the atrogin-1 was strongly induced in muscle in all three models, no changes were observed in the expression of FBXO25. Therefore, here we have shown that FBXO25 is a novel F-box protein analogous to atrogin-1, which is not involved in muscle atrophy. Further functional studies should elucidate the exact role of FBXO25 in the ubiquitin-proteasome pathway.
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PMID:FBXO25, an F-box protein homologue of atrogin-1, is not induced in atrophying muscle. 1671 87

Insulin resistance has been described in several diseases that increase cardiovascular risk and mortality, such as diabetes, obesity, hypertension, metabolic syndrome, and heart failure. Abnormalities of insulin signaling account for insulin resistance. Insulin mediates its action on target organs through phosphorylation of a transmembrane-spanning tyrosine kinase receptor, the insulin receptor (IR). Several mechanisms have been described as responsible for the inhibition of insulin-stimulated tyrosine phosphorylation of IR and the IR substrate (IRS) proteins, including proteasome-mediated degradation, phosphatase-mediated dephosphorylation, and kinase-mediated serine/threonine phosphorylation. In particular, phosphorylation of IRS-1 on serine Ser612 causes dissociation of the p85 subunit of phosphatidylinositol 3-kinase, inhibiting further signaling. On the other hand, phosphorylation of IRS-1 on Ser307 results in its dissociation from the IR and triggers proteasome-dependent degradation. Dysregulation of sympathetic nervous and renin-angiotensin systems resulting in enhanced stimulation of both adrenergic and angiotensin II receptors is a typical feature of several cardiovascular diseases and, at the same time, is involved in the pathogenesis of insulin resistance. The characterization of molecular mechanisms involved in the pathogenesis of insulin resistance may help to design efficacious pharmacologic molecules to treat endothelial and metabolic dysfunction associated with insulin resistance states to reduce the cardiovascular risk and to ameliorate the prognosis of patients with cardiovascular diseases.
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PMID:Insulin resistance and cardiovascular risk: New insights from molecular and cellular biology. 1683 60


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