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)

Renal disease is a common complication of diabetes. The initiating events in diabetic nephropathy are triggered by hyperglycemia and, possibly, advanced glycation end products. Subsequently, excess levels of vasoactive peptides (especially endothelin-1 (ET-1)) accumulate in the diabetic kidney, and there is evidence that these peptides mediate many of the pathophysiological changes associated with diabetic renal disease. These changes include an excess deposition of extracellular matrix proteins into the glomerular basement membrane and renal mesangial cell hypertrophy. Our transcriptional profiling studies have revealed that the p8 gene, which encodes a putative basic helix-loop-helix protein, is strongly induced in ET-1-treated renal mesangial cells and in an animal model of diabetic nephropathy. RNA interference experiments indicated that the p8 gene is required for ET-1-induced mesangial cell hypertrophy. Here, we show that the p8 polypeptide is a phosphoprotein subject to constitutive degradation by the ubiquitin/proteasome system. This degradation is mediated by phosphatidylinositol 3-kinase and protein kinase B/Akt. By contrast, stabilization of the p8 protein requires glycogen synthase kinase-3. Finally, short interfering RNA-mediated RNA interference experiments indicated that ET-1-stimulated mesangial cell hypertrophy and p8 mRNA induction require the NFAT4 transcription factor. Thus, p8 levels in the cell are likely maintained by a balance between signal-dependent transcriptional induction and proteolysis.
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PMID:The pro-hypertrophic basic helix-loop-helix protein p8 is degraded by the ubiquitin/proteasome system in a protein kinase B/Akt- and glycogen synthase kinase-3-dependent manner, whereas endothelin induction of p8 mRNA and renal mesangial cell hypertrophy require NFAT4. 1501 2

A plethora of systemic and local signaling molecules regulate ovarian function, but how different signaling molecules interact within an ovarian target cell is not known. Here we report that endocrine cells of the ovary express a phosphoprotein, DARPP-32 (dopamine and cyclic AMP-regulated phosphoprotein of Mr 32,000), which integrates signaling molecules in neurons. We thus hypothesized that DARPP-32 might act in a similar way in ovarian endocrine cells and therefore studied whether DARPP-32 gene deletion has consequences for ovarian functions in mice. Reproductive performance of adult mutants did not differ from wild-type females, as judged from numbers of litters and pups delivered. Similar steroid levels in mutant and wild-type mice ruled out gross abnormalities in the hypothalamic-pituitary-ovarian axis. However, an analysis of ovarian morphology, using serially sectioned ovaries, revealed several differences. Ovaries of young adult mutant mice at 2 - 3 months contained luteinized follicles, but fewer corpora lutea. At 5 - 6 months, large cysts were found in mutant mice, as well as reduced numbers of preantral follicles and antral follicles. Interstitial cell hypertrophy and degeneration was marked in all mutant ovaries at this age. Thus, while the lack of DARPP-32 does not overtly alter reproductive performance in adult mice, it is associated with progressive alterations and derangements of growth and development of ovarian follicles, suggesting premature ovarian ageing. This implies that ovarian DARPP-32 is involved in follicular development, presumably by integrating effects of signaling molecules, which act together to ensure efficient follicular development.
Exp Clin Endocrinol Diabetes 2004 Sep
PMID:Ovarian function and morphology after deletion of the DARPP-32 gene in mice. 1537 66

Protein phosphorylation constitutes one of the key signaling steps in physiological insulin secretion. The phosphorylation status of a given protein represents the balance of the activities of protein kinases and phosphatases, which induce the addition and removal of phosphate from that protein, respectively. Although several extant studies were focused on the identification and characterization of protein kinases in islets, relatively little information is available on the localization and regulation of protein phosphatases in beta cells. Emerging evidence implicates protein phosphatase 2A (PP2A) in the phenomenon of insulin secretion. The three principal objectives of this commentary are to: (i) review the existing evidence, which suggests regulation, by glucose and other insulin secretagogues, of PP2A in the beta cell; (ii) discuss the experimental evidence, which implicates PP2A-like enzymes in the dephosphorylation and inactivation of key beta cell phosphoprotein substrates (e.g., Akt and Bcl-2), which may be necessary for beta cell proliferation and survival, culminating in the loss of the beta cell mass; and (iii) highlight potential avenues for future research, including the development of specific pharmacological and therapeutic interventional modalities for the inhibition of specific PP2A-like phosphatases for the prevention of loss of beta cell mass leading to the onset of diabetes.
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PMID:Novel regulatory roles for protein phosphatase-2A in the islet beta cell. 1593 44

Reversible phosphorylation is the cell's most prevalent form of posttranslational modification, yet its role in the regulation of mitochondrial functions is poorly understood. We have discovered that a member of the dual-specific protein tyrosine phosphatase (DS-PTP) family, PTPMT1 (PTP localized to the Mitochondrion 1) resides nearly exclusively in mitochondria. PTPMT1 is targeted to the mitochondrion by an N-terminal signal sequence and is found anchored to the matrix face of the inner membrane. Knockdown of PTPMT1 expression in the pancreatic insulinoma cell line INS-1 832/13 alters the mitochondrial phosphoprotein profile and markedly enhances both ATP production and insulin secretion. These data define PTPMT1 as a potential drug target for the treatment of type II diabetes and strengthen the notion that mitochondria are an underappreciated site of signaling by reversible phosphorylation.
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PMID:Involvement of a mitochondrial phosphatase in the regulation of ATP production and insulin secretion in pancreatic beta cells. 1606 Nov 74

Osteopontin (OPN) is a secreted acidic phosphoprotein that binds to a cell-surface integrin-binding motif and is involved in many inflammatory and immune-modulating disorders. There is compelling evidence that soluble OPN can in a variety of situations help cells survive an otherwise lethal insult. In this study we show that OPN is localized in the rat pancreatic islets and ducts. Staining of pancreatic serial sections with islet hormone antibodies showed that all islet cells express OPN. Rats treated with a single dose of streptozotocin (STZ; 50 mg/kg) showed acute upregulation of serum OPN levels and pancreatic OPN mRNA and protein. Serum OPN dropped by the end of day 7 but was still higher than prediabetic levels. Pancreatic mRNA and protein showed a similar pattern. Twenty-four hours after STZ injection, the intensified OPN expression was localized towards the periphery of the islets and surrounded the remaining insulin-positive cells. To explore the significance of OPN acute upregulation, freshly isolated islets were pretreated with OPN (0.15-15 nM) before addition of STZ. OPN significantly reduced the STZ-induced NO levels in the islets through an Arg-Gly-Asp (RGD)-dependent reduction of inducible NO synthase (iNOS) mRNA levels. Addition of OPN to freshly isolated mildly diabetic islets (blood glucose <300 mg/dl) significantly improved their glucose-stimulated insulin secretion and reduced their NO levels. Next we investigated the regulation of OPN in beta-cells. When STZ (5 mM) was added to the beta-cell line RINm5F it significantly increased OPN mRNA levels within 6 h. To distinguish between the effect of STZ and high glucose on OPN transcription, RINm5F cells were transfected with luciferase-labeled rat OPN promoter and treated with STZ (0.05-5 mM) or with glucose (5-25 mM). STZ induced upregulation of OPN promoter activity within 3 h, while high glucose induced upregulation of OPN promoter activity after 48 h. Our data introduce OPN as a novel islet protein that is differentially regulated by STZ and glucose in the islets. OPN initial upregulation after diabetes induction was probably due to STZ-induced toxicity, while maintenance of the high OPN levels might be due to hyperglycemia. The acute induction of OPN after STZ-induced diabetes might represent an endogenous mechanism to protect the islets against STZ-induced cytotoxicity, partly via an RGD-dependent NO regulatory mechanism.
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PMID:Streptozotocin (STZ) mediates acute upregulation of serum and pancreatic osteopontin (OPN): a novel islet-protective effect of OPN through inhibition of STZ-induced nitric oxide production. 1629 71

Human astrocytes express Fas yet are resistant to Fas-induced apoptosis. Here, we report that calcium/calmodulin-dependent protein kinase II (CaMKII) is constitutively activated in human astrocytes and protects the cells from apoptotic stimulation by Fas agonist. Once stimulated, Fas recruits Fas-associated death domain and caspase-8 for the assembly of the death-inducing signaling complex (DISC); however, caspase-8 cleavage is inhibited in the DISC. Inhibition of CaMKII kinase activity inhibits the expression of phosphoprotein enriched astrocytes-15 kDa/phosphoprotein enriched in diabetes (PEA-15/PED) and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (c-FLIP), thus releasing their inhibition of caspase-8 cleavage. Inhibition of PEA-15/PED or c-FLIP by small interfering RNA sensitizes human astrocytes to Fas-induced apoptosis. In contrast, inhibition of CaMKII, PEA-15, or c-FLIP does not affect the sensitivity of human astrocytes to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL death receptors (DR4, DR5) are weakly expressed at mRNA, protein, and cell surface levels and thus fail to mediate the assembly of the DISC in human astrocytes. Overexpression of DR5 restores TRAIL signaling pathways and sensitizes the human astrocytes to TRAIL-induced apoptosis if CaMKII kinase activity or expression of PEA-15 and c-FLIP is inhibited; the results suggest that CaMKII-mediated pathways prevent TRAIL-induced apoptosis in human astrocytes under conditions in which TRAIL death receptors are upregulated. This study has therefore identified the molecular mechanisms that protect normal human astrocytes from apoptosis induced by Fas ligand and TRAIL.
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PMID:Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. 1655 80

A dynamic cycle of O-linked N-acetylglucosamine (O-GlcNAc) addition and removal acts on nuclear pore proteins, transcription factors, and kinases to modulate cellular signaling cascades. Two highly conserved enzymes (O-GlcNAc transferase and O-GlcNAcase) catalyze the final steps in this nutrient-driven "hexosamine-signaling pathway." A single nucleotide polymorphism in the human O-GlcNAcase gene is linked to type 2 diabetes. Here, we show that Caenorhabditis elegans oga-1 encodes an active O-GlcNAcase. We also describe a knockout allele, oga-1(ok1207), that is viable and fertile yet accumulates O-GlcNAc on nuclear pores and other cellular proteins. Interfering with O-GlcNAc cycling with either oga-1(ok1207) or the O-GlcNAc transferase-null ogt-1(ok430) altered Ser- and Thr-phosphoprotein profiles and increased glycogen synthase kinase 3beta (GSK-3beta) levels. Both the oga-1(ok1207) and ogt-1(ok430) strains showed elevated stores of glycogen and trehalose, and decreased lipid storage. These striking metabolic changes prompted us to examine the insulin-like signaling pathway controlling nutrient storage, longevity, and dauer formation in the C. elegans O-GlcNAc cycling mutants. Indeed, we found that the oga-1(ok1207) knockout augmented dauer formation induced by a temperature sensitive insulin-like receptor (daf-2) mutant under conditions in which the ogt-1(ok430)-null diminished dauer formation. Our findings suggest that the enzymes of O-GlcNAc cycling "fine-tune" insulin-like signaling in response to nutrient flux. The knockout of O-GlcNAcase (oga-1) in C. elegans mimics many of the metabolic and signaling changes associated with human insulin resistance and provides a genetically amenable model of non-insulin-dependent diabetes.
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PMID:Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 (O-GlcNAcase) knockout impacts O-GlcNAc cycling, metabolism, and dauer. 1688 29

The phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (ped/pea-15) gene is overexpressed in human diabetes and causes this abnormality in mice. Transgenic mice with beta-cell-specific overexpression of ped/pea-15 (beta-tg) exhibited decreased glucose tolerance but were not insulin resistant. However, they showed impaired insulin response to hyperglycemia. Islets from the beta-tg also exhibited little response to glucose. mRNAs encoding the Sur1 and Kir6.2 potassium channel subunits and their upstream regulator Foxa2 were specifically reduced in these islets. Overexpression of PED/PEA-15 inhibited the induction of the atypical protein kinase C (PKC)-zeta by glucose in mouse islets and in beta-cells of the MIN-6 and INS-1 lines. Rescue of PKC-zeta activity elicited recovery of the expression of the Sur1, Kir6.2, and Foxa2 genes and of glucose-induced insulin secretion in PED/PEA-15-overexpressing beta-cells. Islets from ped/pea-15-null mice exhibited a twofold increased activation of PKC-zeta by glucose; increased abundance of the Sur1, Kir6.2, and Foxa2 mRNAs; and enhanced glucose effect on insulin secretion. In conclusion, PED/PEA-15 is an endogenous regulator of glucose-induced insulin secretion, which restrains potassium channel expression in pancreatic beta-cells. Overexpression of PED/PEA-15 dysregulates beta-cell function and is sufficient to impair glucose tolerance in mice.
Diabetes 2007 Mar
PMID:PED/PEA-15 regulates glucose-induced insulin secretion by restraining potassium channel expression in pancreatic beta-cells. 1732 29

Identification of specific protein phosphorylation sites provides predicative signatures of cellular activity and specific disease states such as cancer, diabetes, Alzheimer disease, and rheumatoid arthritis. Recent progress in phosphopeptide isolation technology and tandem mass spectrometry has provided the means to identify thousands of phosphorylation sites from a single biological sample. These advances now make it possible to profile global changes in the phosphoproteome at an unprecedented level. However, although this technology is generating a wealth of information, there is currently no efficient means to identify phosphoprotein signatures shared among large phosphoprotein databases. Identification of common phosphoprotein signatures found in biologically relevant systems and their conservation throughout evolution would provide valuable insight into mechanisms of signal transduction and cell function. Here we describe the development of a computational program (PhosphoBlast) that can rapidly match thousands of phosphopeptides that share phosphorylation sites within and across species. PhosphoBlast analysis of several large phosphoprotein datasets from the literature revealed common phosphorylation signatures shared across diverse experimental platforms and species. Moreover PhosphoBlast is a powerful analysis tool to identify specific phosphosite mutations. Comparison of the mouse and human phosphoproteomes revealed more than 130 specific phosphoamino acid mutations, some of which are predicted to alter protein function. Further analysis revealed that known phosphorylated amino acids are more evolutionally conserved than the Ser/Thr/Tyr amino acids not known to be phosphorylated. Together our results demonstrate that PhosphoBlast is a versatile mining tool capable of identifying related phosphorylation signatures and phosphoamino acid mutations among complex proteomics datasets in a highly efficient and accurate manner. PhosphoBlast will aid in the informatics analysis of the phosphoproteome and the identification of phosphoprotein biomarkers of disease.
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PMID:PhosphoBlast, a computational tool for comparing phosphoprotein signatures among large datasets. 1793 12

PED (phosphoprotein enriched in diabetes) is a death-effector domain (DED) family member with a broad anti-apoptotic action. PED inhibits the assembly of the death-inducing signalling complex (DISC) of death receptors following stimulation. Recently, we reported that the expression of PED is increased in breast cancer cells and determines the refractoriness of these cells to anticancer therapy. In the present study, we focused on the role of PED in non-small cell lung cancer (NSCLC), a tumour frequently characterized by evasion of apoptosis and drug resistance. Immunohistochemical analysis of a tissue microarray, containing 160 lung cancer samples, indicated that PED was strongly expressed in different lung tumour types. Western blotting performed with specimens from NSCLC-affected patients showed that PED was strongly up-regulated (>6 fold) in the areas of tumour compared to adjacent normal tissue. Furthermore, PED expression levels in NSCLC cell lines correlated with their resistance to tumour necrosis factor related apoptosis-inducing ligand (TRAIL)-induced cell death. The involvement of PED in the refractoriness to TRAIL-induced cell death was investigated by silencing PED expression in TRAIL-resistant NSCLC cells with small interfering (si) RNAs: transfection with PED siRNA, but not with cFLIP siRNA, sensitized cells to TRAIL-induced cell death. In conclusion, PED is specifically overexpressed in lung tumour tissue and contributes to TRAIL resistance.
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PMID:PED is overexpressed and mediates TRAIL resistance in human non-small cell lung cancer. 1828 7


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