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)

FcgammaRIIB1 molecules serve as negative feedback regulator for B cell Ag receptor-elicited activation of B cells; thus, any impaired FcgammaRIIB1 function may possibly be related to aberrant B cell activation. We earlier found deletion polymorphism in the Fcgr2b promoter region among mouse strains in which systemic autoimmune disease-prone NZB, BXSB, MRL, and autoimmune diabetes-prone nonobese diabetic, but not NZW, BALB/c, and C57BL/6 mice have two identical deletion sites, consisting of 13 and 3 nucleotides. In this study, we established congenic C57BL/6 mice for NZB-type Fcgr2b allele and found that NZB-type allele down-regulates FcgammaRIIB1 expression levels in germinal center B cells and up-regulates IgG Ab responses. We did luciferase reporter assays to determine whether NZB-type deletion polymorphism affects transcriptional regulation of Fcgr2b gene. Although NZW- and BALB/c-derived segments from position -302 to +585 of Fcgr2b upstream region produced significant levels of luciferase activities, only a limited activity was detected in the NZB-derived sequence. EMSA and Southwestern analysis revealed that defect in transcription activity in the NZB-derived segment is likely due to absence of transactivation by AP-4, which binds to the polymorphic 13 nucleotide deletion site. Our data imply that because of the deficient AP-4 binding, the NZB-type Fcgr2b allele polymorphism results in up-regulation of IgG Ab responses through down-regulation of FcgammaRIIB1 expression levels in germinal center B cells, and that such polymorphism may possibly form the basis of autoimmune susceptibility in combination with other background contributing genes.
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PMID:Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses. 1237 Mar 66

Islet cell autoantigen 69-kDa (ICA69), protein product of the human ICA1 gene, is one target of the immune processes defining the pathogenesis of Type 1 diabetes. We have characterized the genomic structure and functional promoters within the 5'-regulatory region of ICA1. 5'-RNA ligase-mediated rapid amplification of cDNA ends evaluation of ICA1 transcripts expressed in human islets, testis, heart, and cultured neuroblastoma cells reveals that three 5'-untranslated region exons are variably expressed from the ICA1 gene in a tissue-specific manner. Surrounding the transcription initiation sites are motifs characteristic of non-TATA, non-CAAT, GC-rich promoters, including consensus Sp1/GC boxes, an initiator element, cAMP-responsive element-binding protein (CREB) sites, and clusters of other putative transcription factor sites within a genomic CpG island. Luciferase reporter constructs demonstrate that the first two ICA1 exon promoters reciprocally stimulate luciferase expression within islet- (RIN 1046-38 cells) and brain-derived (NMB7) cells in culture; the exon A promoter exhibits greater activity in islet cells, whereas the exon B promoter more efficiently activates transcription in neuronal cells. Mutation of a CREB site within the ICA1 exon B promoter significantly enhances transcriptional activity in both cell lines. Our basic understanding of expression from the functional core promoter elements of ICA1 is an important advance that will not only add to our knowledge of the ICA69 autoantigen but will also facilitate a rational approach to discover the function of ICA69 and to identify relevant ICA1 promoter polymorphisms and their potential associations with disease.
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PMID:Alternative core promoters regulate tissue-specific transcription from the autoimmune diabetes-related ICA1 (ICA69) gene locus. 1240 89

The critical initiating event in atherogenesis involves the invasion of monocytes through the endothelial wall of arteries, and their transformation from macrophages into foam cells. Human THP-1 monocytic cells can be induced to differentiate into macrophages by phorbol myristate acetate (PMA) treatment, and can then be converted into foam cells by exposure to oxidized low-density lipoprotein (oxLDL). To define genes that are specifically expressed during the transformation of macrophages into foam cells, we have performed a subtractive library screening utilizing mRNA isolated from THP-1 macrophages and foam cells. From this analysis, we have identified adipocyte lipid binding protein (ALBP/aP2) as a gene that is highly upregulated in foam cells in response to oxLDL. Furthermore, overexpression the ALBP gene using an adenovirus construct enhanced the accumulation of cholesterol ester in macrophage foam cells, probably due to an increase in transcription since oxLDL enhanced ALBP promoter activity in experiments using a promoter-luciferase reporter gene construct. The induction of ALBP by oxLDL probably involved activation of peroxisome proliferator-activated receptor gamma (PPARgamma) transcription factors, since four different endogenous PPARgamma ligands, including 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE), two oxidized lipid components of oxLDL, as well as 15-deoxy-delta12,14 prostaglandin J2 (15d-PGJ2) and retinoic acid (RA), all induced ALBP expression in macrophage/foam cells. Finally, ALBP was found to be highly expressed in vivo in macrophage/foam cells of human atherosclerotic plaques. These observations suggest that oxLDL-mediated increase in ALBP gene expression accelerate cholesterol ester accumulation, and that this is an important component of the genetic program regulating conversion of macrophages to foam cells. The observation that ALBP is readily detected in foam cells in active atherosclerotic lesions implicates a role for ALBP in human vascular disease. The induction of ALPB expression by oxLDL likely involves activation of PPARgamma by components of oxLDL (9-HODE and 13-HODE) that also function as PPARgamma ligands. Our results add to the concern that the clinical use of insulin-sensitizing PPARgamma agonists (i.e. thiazolidinediones) to treat Type 2 Diabetes could exacerbate atherosclerosis, and highlight the need for clinical trials that address this issue.
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PMID:The adipocyte lipid binding protein (ALBP/aP2) gene facilitates foam cell formation in human THP-1 macrophages. 1241 76

Previous studies have shown that renal function in type 2 diabetes correlates better with tubular changes than with glomerular pathology. Since advanced glycation end products (AGEs; AGE-albumin) and in particular carboxymethyllysine (CML) are known to play a central role in diabetic nephropathy, we studied the activation of nuclear factor kappaB (NF-kappaB) in tubular epithelial cells in vivo and in vitro by AGE-albumin and CML. Urine samples from healthy control subjects (n = 50) and type 2 diabetic patients (n = 100) were collected and tested for excretion of CML and the presence of proximal tubular epithelial cells (pTECs). CML excretion was significantly higher in diabetic patients than in healthy control subjects (P < 0.0001) and correlated with the degree of albuminuria (r = 0.7, P < 0.0001), while there was no correlation between CML excretion and HbA(1c) (r = 0.03, P = 0.76). Urine sediments from 20 of 100 patients contained pTECs, evidenced by cytokeratin 18 positivity, while healthy control subjects (n = 50) showed none (P < 0.0001). Activated NF-kappaB could be detected in the nuclear region of excreted pTECs in 8 of 20 patients with pTECs in the urine sediment (40%). Five of eight NF-kappaBp65 antigen-positive cells stained positive for interleukin-6 (IL-6) antigen (62%), while only one of the NF-kappaB-negative cells showed IL-6 positivity. pTECs in the urine sediment correlated positively with albuminuria (r = 0.57, P < 0.0001) and CML excretion (r = 0.55, P < 0.0001). Immunohistochemistry in diabetic rat kidneys and a human diabetic kidney confirmed strong expression of NF-kappaB in tubular cells. To further prove an AGE/CML-induced NF-kappaB activation in pTECs, NF-kappaB activation was studied in cultured human pTECs by electrophoretic mobility shift assays (EMSAs) and Western blot. Stimulation of NF-kappaB binding activity was dose dependent and was one-half maximal at 250 nmol/l AGE-albumin or CML and time dependent at a maximum of activation after 4 days. Functional relevance of the observed NF-kappaB activation was demonstrated in pTECs transfected with a NF-kappaB-driven luciferase reporter plasmid and was associated with an increased release of IL-6 into the supernatant. The AGE- and CML-dependent activation of NF-kappaBp65 and NF-kappaB-dependent IL-6 expression could be inhibited using the soluble form of the receptor for AGEs (RAGE) (soluble RAGE [sRAGE]), RAGE-specific antibody, or the antioxidant thioctic acid. In addition transcriptional activity and IL-6 release from transfected cells could be inhibited by overexpression of the NF-kappaB-specific inhibitor kappaBalpha. The findings that excreted pTECs demonstrate activated NF-kappaB and IL-6 antigen and that AGE-albumin and CML lead to a perpetuated activation of NF-kappaB in vitro infer that a perpetuated increase in proinflammtory gene products, such as IL-6, plays a role in damaging the renal tubule.
Diabetes 2002 Dec
PMID:Activation of tubular epithelial cells in diabetic nephropathy. 1245 11

LOT1 is a zinc-finger nuclear transcription factor, which possesses anti-proliferative effects and is frequently silenced in ovarian and breast cancer cells. The LOT1 gene is localized at chromosome 6q24-25, a chromosomal region maternally imprinted and linked to growth retardation in several organs and progression of disease states such as transient neonatal diabetes mellitus. Toward understanding the molecular mechanism underlying the loss of LOT1 expression in cancer, we have characterized the genomic structure and analyzed its epigenetic regulation. Genome mapping of LOT1 in comparison with the other splice variants, namely ZAC1 and PLAGL1, revealed that its mRNA ( approximately 4.7 kb; GenBank accession number U76261) is potentially spliced using six exons spanning at least 70 kb of the human genome. 5'-RACE (rapid amplification of cDNA ends) data indicate the presence of at least two transcription start sites. We found that in vitro methylation of the LOT1 promoter causes a significant loss in its ability to drive luciferase transcription. To determine the nature of in vivo methylation of LOT1, we used bisulfite-sequencing strategies on genomic DNA. We show that in the ovarian and breast cancer cell lines and/or tumors the 5'-CpG island of LOT1 is a differentially methylated region. In these cell lines the ratio of methylated to unmethylated CpG dinucleotides in this region ranged from 31 to 99% and the ovarian tumors have relatively higher cytosine methylation than normal tissues. Furthermore, we show that trichostatin A, a specific inhibitor of histone deacetylase, relieves transcriptional silencing of LOT1 mRNA in malignantly transformed cells. It appears that, unlike DNA methylation, histone deacetylation does not target the promoter, and rather it is indirect and may be elicited by a mechanism upstream of the LOT1 regulatory pathway. Taken together, the data suggest that expression of LOT1 is under the control of two epigenetic modifications and that, in the absence of loss of heterozygosity, the biallelic (two-hit) or maximal silencing of LOT1 requires both processes.
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PMID:LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24-25, is epigenetically regulated in cancer. 1247 47

The purpose of the current study was to determine whether nuclear factor-kappaB (NF-kappaB) activation is a component of the depolarization/Ca(2+)-dependent signaling in beta-cells. MIN6 cells were transfected with a plasmid containing five tandem repeats of NF-kappaB binding sites linked to a luciferase reporter. The results of these experiments showed that KCl induced depolarization-activated NF-kappaB-dependent transcription (3.8-fold at 45 mmol/l, P < 0.01) in a concentration-dependent manner. Tumor necrosis factor-alpha (TNF-alpha), a known inducer of NF-kappaB signaling, activated this construct by 3.4-fold (P < 0.01). The response of NF-kappaB to depolarization was inhibited by the Ca(2+)-channel blocker verapamil and by the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059 (70 and 62%, respectively). TNF-alpha, glucose, and KCl treatment resulted in inhibitory kappaBalpha degradation by Western blot analysis. TNF-alpha treatment and depolarization activation of NF-kappaB differed significantly in that TNF-alpha activation was not blocked by PD98059. Transfection with PKA, MEK, and MEK kinase induced NF-kappaB-dependent transcription by 20-, 90-, and 300-fold, respectively, suggesting that these pathways contribute to the activation in the depolarization response. These findings demonstrate that depolarization/Ca(2+) influx, as well as TNF-alpha treatment, can activate NF-kappaB-dependent transcription in pancreatic beta-cells, but by different signaling pathways. The current studies show that Ca(2+) signals in pancreatic beta-cells can activate transcription factors involved in the regulation of cell cycle and apoptosis. These findings now add NF-kappaB to the list of depolarization-induced transcription factors in pancreatic beta-cells.
Diabetes 2002 Dec
PMID:Activation of nuclear factor-kappaB by depolarization and Ca(2+) influx in MIN6 insulinoma cells. 1247 94

There is increasing evidence implicating genetic factors in the susceptibility to diabetic microvascular complications. Recent studies suggest that increased expression of the cytokine vascular endothelial growth factor (VEGF) may play a role in the pathogenesis of diabetic complications. A number of polymorphisms in the promoter region of the VEGF gene have been identified. The aim was to investigate whether an 18 base pair (bp) deletion (D)/insertion (I) polymorphism at position -2549 in the promoter region of the VEGF gene is associated with the susceptibility to diabetic microvascular complications. Two hundred and thirty-two patients with type 1 diabetes mellitus (T1DM) and 141 normal healthy controls were studied. The D/D genotype was significantly increased in those patients with nephropathy (n=102) compared to those with no complications after 20 years duration of diabetes (uncomplicated, n=66) (40.2% vs. 22.7%, respectively, chi(2)=5.5, P<.05). The combination of polymorphisms of VEGF together with the aldose reductase (ALR2) gene showed that in the nephropaths, 8 of the 83 subjects had the VEGF I allele together with the Z+2 5'ALR2 allele compared with 27 of the 62 uncomplicated patients (chi(2)=26.7, P<.00001). The functional role of the D/I polymorphism was examined by cloning the region into a luciferase reporter assay system and transient transfection into HepG2 cells. The construct containing the 18 bp deletion had a 1.95-fold increase in transcriptional activity compared with its counterpart that had the insert (P<.01). These results suggest that polymorphisms in the promoter region of the VEGF gene together with the ALR2 may be associated with the pathogenesis of diabetic nephropathy.
J Diabetes Complications
PMID:Polymorphisms of the vascular endothelial growth factor and susceptibility to diabetic microvascular complications in patients with type 1 diabetes mellitus. 1250 48

We have previously reported that high glucose stimulates osteopontin (OPN) expression via a protein kinase C-dependent pathway and a hexosamine pathway in cultured rat aortic smooth muscle cells (SMCs) [Biochem. Biophys. Res. Commun. 258 (1999) 722.]. In the present study, we carried out functional OPN promoter assays using the luciferase expression vector system in cultured rat aortic SMCs to determine a high glucose/glucosamine responsive element. An extensive deletion analysis of the 5'-flanking region of the rat OPN gene revealed that an element involved in high glucose and glucosamine responses was present within a region between -112 and -62 bp of the OPN promoter. This region is highly conserved in the rat, mouse, and human promoters and contains a number of consensus regions, including an E-box and a GC-rich region. Mutation of the E-box or the GC-rich region resulted in a significant loss of both high glucose and glucosamine responses. These results suggest that two cis-acting elements, the E-box and the GC-rich region, are involved at least partly in high glucose/glucosamine-stimulated transcription of the rat OPN gene.
J Diabetes Complications
PMID:Identification and characterization of high glucose and glucosamine responsive element in the rat osteopontin promoter. 1250 55

Pancreatic beta-cells are selectively destroyed during the course of type 1 diabetes. In the early stages of the disease, inflammatory infiltrates of mononuclear cells, containing predominantly monocytes and T-cells, are present in the islets (insulitis). Chemokines, such as monocyte chemoattractant protein-1 (MCP-1), play a key role in the recruitment and activation of these immunocytes. We have previously described cytokine-induced MCP-1 gene expression in human and rat pancreatic islets. In the present study, the transcriptional regulation by cytokines of the rat MCP-1 gene in fluorescence-activated cell sorting-purified rat beta-cells, insulin-producing INS-1E cells, and RINm5F cells was investigated. Transient transfections with luciferase-reporter constructs identified an interleukin (IL)-1beta-responsive enhancer region between -2,180 bp and -2,478 bp. Mutation of either of the two nuclear factor (NF)-kappaB sites present in this region abrogated IL-1beta-induced MCP-1 promoter activity. Binding of NF-kappaB to the two sites was shown in vitro by gel shift assays, while supershift assays revealed the presence of p65/p50 heterodimers and p65 homodimers. In vivo binding of NF-kappaB was confirmed by chromatin immunoprecipitation assay. Blocking of NF-kappaB activation in cytokine-exposed primary beta-cells by an adenovirus overexpressing a nondegradable form of IkappaBalpha or by pyrrolidine dithiocarbamate decreased IL-1beta-induced MCP-1 mRNA expression. We conclude that NF-kappaB plays an important role for MCP-1 expression in beta-cells. This transcription factor may be an interesting target for ex vivo gene therapy before islet transplantation.
Diabetes 2003 Feb
PMID:Molecular regulation of monocyte chemoattractant protein-1 expression in pancreatic beta-cells. 1254 Jun 7

The proglucagon gene encodes pancreatic glucagon and the glucagon-like peptides, which exert diverse effects on nutrient absorption and assimilation. The therapeutic potential of glucagon-like peptide-1 (GLP-1) has fostered interest in development of cellular engineering approaches to augment endogenous intestinal-derived GLP-1 for the treatment of type 2 diabetes. We have used adenovirus technology to examine the potential roles of the transcription factors Cdx-2/3 and Pax-6 as activators of endogenous proglucagon gene expression in enteroendocrine cell lines and in nontransformed rat intestinal cells. Adenoviral-expressed Cdx-2/3 and Pax-6 activated proglucagon promoter-luciferase activity in baby hamster kidney (BHK) fibroblasts, HEK 293 cells, and enteroendocrine cell lines. Pax-6, but not Cdx-2/3, induced expression of the endogenous proglucagon gene in enteroendocrine cell lines, but not in heterologous fibroblasts. Furthermore, transduction of primary rat intestinal cell cultures in vitro, or the rat colonic epithelium in vivo, with Ad-Pax-6 activated endogenous proglucagon gene expression. These data demonstrate that Pax-6, but not Cdx-2/3, is capable of activating the endogenous proglucagon gene in both immortalized enteroendocrine cells and the nontransformed intestinal epithelium in vivo.
Diabetes 2003 Feb
PMID:Pax-6 activates endogenous proglucagon gene expression in the rodent gastrointestinal epithelium. 1254 Jun 17


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