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)

Posttranslational protein modifications are effective devices that cells use to control the functions of proteins. Ubiquitin-like protein modifiers (Ubls) are posttranslationally attached to proteins by enzymatic reactions that are similar to ubiquitin conjugation. SUMO (small ubiquitin-related modifier) family proteins are the most intriguing Ubls. Sumoylation is the covalent attachment of SUMO to target proteins. Neddylation is the process that conjugates the ubiquitin-like polypeptide Nedd8 to the conserved lysines of cullins. Cullin family proteins organize ubiquitin ligase complexes to target numerous cellular proteins for polyubiquitinylation and subsequent proteasomal degradation. Despite the similarities in their structure and in enzymatic reactions Ubls and ubiquitin have distinct functions. In contrast with polyubiquitinylation that targets modified proteins to proteasome degradation, the biological consequences of sumoylation include the increase of protein stability. Sumoylation also helps in the protein transport from the cytoplasm to nucleus of cells, regulates transcriptional activities of proteins and mediates the binding of the protein to other proteins. Neddylation has importance for cell cycle control, signal transmission, cell differentiation and DNA repair. Recent studies linked sumoylation and neddylation of several proteins to important diseases (neurodegenerative diseases, acute promyelocytic leukemia, type I diabetes and other disorders). The regulation of these postranslational modifications may provide new targets for therapeutic intervention in several human diseases.
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PMID:[Ubiquitins, proteasomes, sumoylation and application today and in future for cancer and other diseases therapy II. Sumoylation and neddylation as posttranslational modifications of proteins and their ubiquitinylation and its significance]. 1687 67

HIV-1 protease inhibitors have revolutionized the treatment of HIV infection, but their use has been associated with lipodystrophy and insulin resistance. One suggestion for this has been the inhibition of insulin-degrading enzyme (IDE). We have previously demonstrated that insulin, through IDE, can inhibit the proteasome, thus decreasing cytosolic protein degradation. We examined whether the protease inhibitor nelfinavir inhibited IDE and its effect on protein degradation both in vitro and in whole cells. 125I-Insulin degradation was measured by trichloroacetic acid precipitation. Proteasome activities were measured using fluorogenic peptide substrates. Cellular protein degradation was measured by prelabelling cells with 3H-leucine and determining the release of TCA-soluble radioactivity. Nelfinavir inhibited IDE in a concentration-dependent manner with 50% inhibition at the maximal concentration tested, 100 microm. Similarly, the chymotrypsin-like and trypsin-like activities of the proteasome were decreased with an IC50 of approximately 3 microm. The ability of insulin to inhibit the proteasome was abrogated by nelfinavir. Treatment of HepG2 cells with 50 microm nelfinavir decreased 125I-insulin degradation and increased cell-associated radioactivity. Insulin alone maximally decreased protein degradation by 15%. Addition of 50 microm nelfinavir inhibited cellular protein degradation by 14% and blunted the effect of insulin. These data show that nelfinavir inhibits IDE, decreases insulin's ability to inhibit protein degradation via the proteasome and provides another possible mechanism for the insulin resistance seen in protease inhibitor-treated HIV patients.
Diabetes Obes Metab 2006 Nov
PMID:Effect of nelfinavir on insulin metabolism, proteasome activity and protein degradation in HepG2 cells. 1702 90

Neuronal homoeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the UPS (ubiquitin-proteasome system). As a result of molecular misreading, misframed UBB (ubiquitin B) (UBB+1) is generated. UBB+1 accumulates in the neuritic plaques and neurofibrillary tangles in all patients with AD (Alzheimer's disease) and in the neuronal and glial hallmarks of other tauopathies and in polyglutamine diseases such as Huntington's disease. UBB+1 is not present in synucleinopathies such as Parkinson's disease. We showed that UBB+1 causes UPS dysfunction, aggregation and apoptotic cell death. UBB+1 is also present in non-neurological cells, hepatocytes of the diseased liver and in muscles during inclusion body myositis. Other frequently occurring (age-related) diseases such as Type 2 (non-insulin-dependent) diabetes mellitus are currently under investigation. These findings point to the importance of the UPS in diseases and open new avenues for target identification of the main players of the UPS. Treatment of these diseases with tools (e.g. viral RNA interference constructs) to intervene with specific targets is the next step.
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PMID:Molecular misreading: the occurrence of frameshift proteins in different diseases. 1705 86

It has been shown that store-operated Ca(2+) influx (SOC) plays critical roles in the activation of endothelial nitric oxide (NO) synthase (eNOS) and generation of NO in endothelial cells. Recent studies indicate stromal interaction molecule 1 (STIM1) is the molecule responsible for SOC activation following Ca(2+) depletion in the ER. Retinoic acids (RA) have beneficial effects in the treatment of renal diseases. The mechanism of the RA action is still largely unknown. In the current study, we used primary cultured rat mesangial cells to examine the effect of RA on SOC and STIM1. In these cells, BK caused concentration-dependent [Ca(2+)](i) mobilization. Treatment of the cells with RA, while it had no effect on the initial peak, reduced the plateau phase of BK-mediated [Ca(2+)](i) response, indicating the inhibition of SOC by RA. The level of STIM1 protein but not mRNA in RA-treated cells was significantly reduced. RA treatment did not affect TGF-beta-mediated gradual Ca(2+) influx which occurred by superoxide anion-mediated mechanism, indicating RA treatment specifically inhibited SOC in mesangial cells. RT-PCR and Western blot analysis demonstrated that eNOS was expressed in rat mesangial cells grown in media containing 11 and 30 but not 5.5 mM glucose. Downregulation of STIM1 protein and BK-induced SOC by RA treatment or STIM1 dsRNA were associated with abolished NO production. The 26S proteasome inhibitor lactacystin blocked the RA-mediated downregulation of BK-induced SOC, suggesting that ubiquitin-proteasome pathway may be involved in RA-mediated STIM1 protein downregulation in rat mesangial cells. Our data suggest that glucose-induced eNOS expression and NO production in mesangial cells may contribute to hyperfiltration in diabetes and RA may exert beneficial effects by downregulation of STIM1 and SOC in mesangial cells.
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PMID:Regulation of STIM1, store-operated Ca2+ influx, and nitric oxide generation by retinoic acid in rat mesangial cells. 1709 Jul 80

Peroxisome proliferator-activated receptor (PPAR) alpha, gamma, and delta belong to the nuclear hormone receptor superfamily of ligand-activated transcription factors. PPARs regulate metabolic, developmental, and differentiation pathways and play important roles in human diseases, such as diabetes, atherosclerosis, cancer, and chronic inflammation. PPARs are the targets of drugs of widespread clinical use and represent promising targets for discovery of new therapeutics. The interaction of PPARs with the ubiquitin-proteasome system (UPS) has been the subject of limited investigation. The UPS plays an important role in regulating the levels and modulating ligand-dependent and-independent activity of nuclear receptors. This review highlights the current knowledge regarding the interactions of the UPS with PPARs and focuses on the differential regulation of the level and activity of the PPAR isotypes by the UPS in response to selective ligands. Understanding the connections between the UPS and PPARs can provide insights in the actions of existing drugs and raise the possibilities for development of more effective PPAR-based therapeutics.
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PMID:Control of peroxisome proliferator-activated receptor fate by the ubiquitinproteasome system. 1711 5

Insulin deficiency is known to be associated with a state of increased muscle protein breakdown; this process is mediated by the ubiquitin-proteasome pathway. Convincing in vitro data are further supported by extensive studies in humans with insulin deprivation and are further substantiated by reversal of muscle protein breakdown with insulin treatment. In patients with end-stage renal disease (ESRD) and diabetes mellitus (DM), muscle protein breakdown is enhanced in both acute and chronic conditions. Recent data also point to the potential protein catabolic effects of insulin resistance combined with insulin deficiency. Because ESRD is associated with a state of insulin resistance, uremic muscle wasting may also be mediated by this pathway.
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PMID:Effects of glucose homeostasis on protein metabolism in patients with advanced chronic kidney disease. 1719 26

Diabetes-induced oxidative stress can lead to protein misfolding and degradation by the ubiquitin-proteasome system. This study examined protein ubiquitination in pancreatic sections from Zucker diabetic fatty rats. We observed large aggregates of ubiquitinated proteins (Ub-proteins) in insulin-expressing beta-cells and surrounding acinar cells. The formation of these aggregates was also observed in INS1 832/13 beta-cells after exposure to high glucose (30 mmol/l) for 8-72 h, allowing us to further characterize this phenotype. Oxidative stress induced by aminotriazole (ATZ) was sufficient to stimulate Ub-protein aggregate formation. Furthermore, the addition of the antioxidants N-acetyl cysteine (NAC) and taurine resulted in a significant decrease in formation of Ub-protein aggregates in high glucose. Puromycin, which induces defective ribosomal product (DRiP) formation was sufficient to induce Ub-protein aggregates in INS1 832/13 cells. However, cycloheximide (which blocks translation) did not impair Ub-protein aggregate formation at high glucose levels, suggesting that long-lived proteins are targeted to these structures. Clearance of Ub-protein aggregates was observed during recovery in normal medium (11 mmol/l glucose). Despite the fact that 20S proteasome was localized to Ub-protein aggregates, epoxomicin treatment did not affect clearance, indicating that the proteasome does not degrade proteins localized to these structures. The autophagy inhibitor 3MA blocked aggregate clearance during recovery and was sufficient to induce their formation in normal medium. Together, these findings demonstrate that diabetes-induced oxidative stress induces ubiquitination and storage of proteins into cytoplasmic aggregates that do not colocalize with insulin. Autophagy, not the proteasome, plays a key role in regulating their formation and degradation. To our knowledge, this is the first demonstration that autophagy acts as a defense to cellular damage incurred during diabetes.
Diabetes 2007 Apr
PMID:Ubiquitinated-protein aggregates form in pancreatic beta-cells during diabetes-induced oxidative stress and are regulated by autophagy. 1739 40

The kidney undergoes hypertrophy under conditions that paradoxically cause a loss of lean body mass, such as diabetes, acidosis, and chronic kidney disease. What unique mechanisms account for kidney growth during negative nitrogen balance? One adaptation is that renal tubular cells substantially decrease protein breakdown during kidney cell growth. In this review, we discuss how acidosis and diabetes reduce protein breakdown within the kidney and the intracellular signaling pathways that may regulate protein metabolism. Our results suggest that in cell culture models and in acute diabetes, kidney cells specifically reduce protein breakdown by the lysosomal pathway of chaperone-mediated autophagy. This differs from the activation of proteolysis by the ubiquitin-proteasome system in muscle in acute diabetes and uremia. A shared signaling pathway regulates protein breakdown in both kidney and skeletal muscle, namely, phosphatidylinositol-3 kinase signaling. Diabetes mellitus activates signaling through this pathway in the kidney while down-regulating it in skeletal muscle. We conclude that similar signaling pathways may regulate distinct proteolytic pathways in different tissues.
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PMID:Kidney growth during catabolic illness: what it does not destroy makes it grow stronger. 1746 48

Ligand binding grooves of MHC class I molecules are able to load a panel of endogenous peptides of varying length and sequence derived from self or foreign origin to activate or deactivate cytotoxic CD8(+) T cells. Peptides are assembled with class I molecules by pathways that are either dependent or independent of transport by ABC proteins (TAP) and degradation in the immunoproteasome by its subunits LMP2 and LMP7. Those peptides that require TAP and LMP treatment appear to be subject to control and optimization by TAP for proper customizing and efficient presentation. Therefore, allelic variations in the coding sequences of TAP and LMP were suspected for a long time to be responsible for improper antigen processing, interruption of self-peptide presentation and reduced cell surface expression of MHC class I molecules resulting in the activation of autoreactive CD8(+) T cells. In this article we reviewed the controversial findings regarding the role of TAP and LMP genes in autoimmune diabetes and reevaluated data of eleven separate studies in a cross-study analysis by genotype and HLA haplotype matching. We could confirm previous results by showing that TAP2*651-A/F and TAP2*687-A/A are significantly associated with disease, independently of linkage disequilibrium (LD). LMP2-R/H surprisingly seems to be primarily disease-conferring although a weak association with DR4 serotypes can be observed. Our analysis also suggests that LMP7-B/B, TAP1-A/A and TAP2*687-A/B are the protective genotypes and that these associations are not secondary to LD with DRB1. Consequently, intracellular antigen processing associated with TAP- and proteasome-dependent pathways seems to be a critical element in T cell selection for the retention of a balanced immunity.
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PMID:Genetic susceptibility to type 1 diabetes in the intracellular pathway of antigen processing - a subject review and cross-study comparison. 1749 58

Multiple genome-wide scans in different populations have linked the chromosome 12q24 region, known as NIDDM2 (non-insulin-dependent-diabetes, locus 2), to type 2 diabetes. Within NIDDM2 we examined the PSMD9 (proteasome modulator 9/Bridge-1) gene that encodes a PDZ-domain transcriptional coactivator of insulin production. Our goal was to identify a potential contribution of the PSMD9 gene to type 2 diabetes in Italians. We directly sequenced the entire gene PSMD9 in Italian type 2 diabetes patients (n = 237) and controls subjects (n = 215) and performed an association study with the identified gene variants. We found five single nucleotide polymorphisms (SNPs), A17V, IVS1+nt29, IVS3+nt460, IVS3+nt437, and E197G, which are not associated with disease in our case-control study. Furthermore, we identified two PSMD9 gene variants in type 2 diabetes patients, which produced nonconservative amino acid substitutions S143G and N166S within the PDZ domain and two other gene variants. Three out of four of these variants are absent from the control subjects screened. We propose that the three PSMD9 gene variants (S143G, N166S and G > A at IVS3+nt102), absent in control subjects, contribute rarely to late-onset type 2 diabetes in Italians. In fact, the frequency rate of such variants in unrelated cases equals 0.016. We may not exclude that PSMD9 gene variants may contribute, either commonly or rarely, to an increased risk of type 2 diabetes in other populations.
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PMID:PSMD9 gene variants within NIDDM2 may rarely contribute to type 2 diabetes. 1751 68


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