Unusual DNA structure of the diabetes susceptibility locus
            <i>IDDM2</i>
            and its effect on transcription by the insulin promoter factor Pur-1/MAZ

Lew, Amy; Rutter, William J.; Kennedy, Giulia C.

doi:10.1073/pnas.97.23.12508

Cited by 102 publications

(112 citation statements)

References 32 publications

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“…In contrast, using transfected beta cells, class I ILPR alleles were found to be transcriptionally less active than class III alleles [86]. Furthermore, variations within each repeat at IDDM2 also correlated with insulin mRNA levels in heterozygous individuals [87] as well as with transcriptional activity in transfection experiments [88].…”

Section: Ilpr (Vntr Hvr)mentioning

confidence: 82%

Regulation of insulin gene transcription

2002

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Insulin, synthesized by the beta cells of pancreatic islets, is of major physiological importance in metabolic homeostasis. While mature insulin consists of two polypeptide chains joined by disulphide bridges, the gene encodes for a highly conserved single chain precursor, preproinsulin [1]. In most species preproinsulin exists as a single gene, whereas in the mouse and the rat two non-allelic insulin genes are present. The human insulin gene is located on the short arm of chromosome 11 (p15.5) [2], the rat insulin I and II genes are colocalized on chromosome 1 [3] and the mouse genes are positioned on two different chromosomes, insulin I on chromosome 19 [4] and insulin II on chromosome 7 [5]. In adult islets, the nonallelic genes appear to be coordinately expressed and regulated [6, 7]. The rodent insulin II and the human genes contain three exons and two introns, whilst insulin I lacks the second intron. The organisation and structure of the insulin gene has been reviewed in detail [8]. Insulin is regulat- AbstractThe mammalian insulin gene is exclusively expressed in the beta cells of the endocrine pancreas. Two decades of intensive physiological and biochemical studies have led to the identification of regulatory sequence motifs along the insulin promoter and to the isolation of transcription factors which interact to activate gene transcription. The majority of the islet-restricted (BETA2, PDX-1, RIP3b1-Act/C1) and ubiquitous (E2A, HEB) insulin-binding proteins have been characterized. Transcriptional regulation results not only from specific combinations of these activators through DNA-protein and protein-protein interactions, but also from their relative nuclear concentrations, generating a cooperativity and transcriptional synergism unique to the insulin gene. Their DNA binding activity and their transactivating potency can be modified in response to nutrients (glucose, NEFA) or hormonal stimuli (insulin, leptin, glucagon like peptide-1, growth hormone, prolactin) through kinase-dependent signalling pathways (PI3-K, p38MAPK, PKA, CaMK) modulating their affinities for DNA and/or for each other. From the overview of the research presented, it is clear that much more study is required to fully comprehend the mechanisms involved in the regulated-expression of the insulin gene in the beta cell to prevent its impairment in diabetes. [Diabetologia (2002) 45: 309±326]

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Section: Ilpr (Vntr Hvr)mentioning

confidence: 82%

Regulation of insulin gene transcription

2002

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“…The class III allele is associated with a reduction of insulin transcription in the fetal (4) and adult pancreas (5). The observation that INS-VNTR acts as a binding site to the transcription factor Pur1 (27) forms a potential basis of these functional relationships (29).…”

Section: Discussionmentioning

confidence: 99%

The Insulin Gene Variable Number Tandem Repeat Class I/III Polymorphism Is in Linkage Disequilibrium With Birth Weight but Not Type 2 Diabetes in the Pima Population

et al. 2003

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The insulin gene variable number tandem repeat (INS-VNTR) is proposed to exert pleiotropic genetic effects on birth weight and diabetes susceptibility. In our study, we examined the influence of a polymorphism in tight linkage disequilibrium with INS-VNTR (؊23Hph1) on birth weight and type 2 diabetes in the Pima population. A parent-offspring "trio" design was used to assess parent-of-origin effects and population stratification. The presence of the -23Hph1 T-allele was associated with lower birth weight (n ‫؍‬ 192; ؊140 g per copy of the T-allele; P ‫؍‬ 0.04), even after adjustment for effects of population stratification (P ‫؍‬ 0.03). The effects of paternally transmitted T-alleles were greater than those of maternally transmitted alleles (paternally transmitted: -250 g, P ‫؍‬ 0.05; maternally transmitted: -111 g, P ‫؍‬ 0.43), but this difference was not statistically significant (P ‫؍‬ 0.50). The ؊23Hph1 T-allele was associated with an increased prevalence of type 2 diabetes (P ‫؍‬ 0.009), which family-based association analysis suggested was attributable to population structure (P ‫؍‬ 0.04) without significant evidence of linkage disequilibrium between diabetes prevalence and genotype (P ‫؍‬ 0.86). Thus allelic variation of the INS gene is associated with lower birth weight and increased prevalence of type 2 diabetes. Significant linkage disequilibrium was found between -23Hph1 and birth weight but not type 2 diabetes, an observation that supports a potential functional role of INS polymorphisms in the regulation of birth weight. Diabetes 52: [187][188][189][190][191][192][193] 2003

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“…One possibility is that alterations of MNs, located upstream or downstream of genes, could affect their expression levels. 36,37) In order to clarify further the biological relevance of MN mutations in carcinogenesis, studies should be conducted to identify specific genes, whose structure and/or expression are altered by MN mutations in cancer cells. January 19, 2002) …”

Section: Discussionmentioning

confidence: 99%

Frequent and Multiple Mutations at Minisatellite Loci in Sporadic Human Colorectal and Gastric Cancers—Possible Mechanistic Differences from Microsatellite Instability in Cancer Cells

Inamori

Takagi

Tajima

et al. 2002

Japanese Journal of Cancer Research

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Minisatellites (MNs), composed of 5 to 100 nucleotide repeat units, range from 0.5 to 30 kb in length, and have been reported to be mutated in various human malignancies. In this study, frequencies of MN mutations in sporadic human colorectal (34 cases) and gastric cancers (24 cases) at various clinicopathological stages were assessed by multilocus DNA fingerprint analysis with three MN probes, Pc-1, 33.6 and 33.15. MN mutations were observed in both colorectal and gastric cancers, but at a significantly higher frequency in the former (56%) than in the latter (25%). Multiplicities of MN mutations were 1.50 ± ± ± ±1.81 and 0.46± ± ± ±1.10 in colorectal and gastric cancers, respectively, and the difference was also significant. Neither the presence nor multiplicity of MN mutations in either colorectal or gastric cancer cases had any correlation with the pathological stage, histological grading or the presence of microsatellite instability (MSI). Although the biological relevance of MN mutations still remains to be clarified, a subset of colorectal and gastric cancers could feature a new type of genomic instability, distinct from MSI. Key words: DNA fingerprint analysis -Colorectal cancer -Minisatellite mutation -Minisatellite instability -Microsatellite instabilityIt has recently been proposed that at least two types of genomic instability underlie human colorectal cancers; namely, microsatellite instability (MSI) and chromosomal instability (CIS).1, 2) Mutations in mismatch repair genes lead to MSI in hereditary nonpolyposis colorectal cancer and a subset of sporadic colorectal cancers, 1, 3) and mutations in genes involved in the mitotic checkpoint, such as BUB1 and hCHK2 genes, could result in CIS. 4,5) Long tracts of mononucleotides in the transforming growth factor-β type II receptor, BAX and insulin-like growth factor II receptor genes are the targets of MSI, and they are frequently mutated.6-8) Most of the mutations are of the frameshift type that result in inactivation of the gene products, potentially contributing to the proliferative properties of cancer cells. Recently, defects in mismatch repair were also demonstrated to promote telomerase-independent cell proliferation in yeast. 9)Minisatellites (MNs), also called variable number of tandem repeats (VNTRs), are another type of repetitive sequence of which a few thousand copies exist per haploid genome of mammalian cells. 10) They are composed of 5 to 100 nucleotide repeat units, range from 0.5 to 30 kb in length and are dispersed throughout the entire genome of all vertebrates, being preferentially located on the telomeric sides of human chromosomes.11) A subset of MN demonstrates considerably high mutation rates in germ cells, constituting hot spots for meiotic recombination, 12) even though most MNs are comparatively stable in somatic cells. Although several studies have already demonstrated alteration of MN (MN mutations) in various human neoplasms, [13][14][15][16] to our knowledge no extensive analysis has been performed with regard to the relatio...

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Unusual DNA structure of the diabetes susceptibility locus IDDM2 and its effect on transcription by the insulin promoter factor Pur-1/MAZ

Cited by 102 publications

References 32 publications

Regulation of insulin gene transcription

Regulation of insulin gene transcription

The Insulin Gene Variable Number Tandem Repeat Class I/III Polymorphism Is in Linkage Disequilibrium With Birth Weight but Not Type 2 Diabetes in the Pima Population

Frequent and Multiple Mutations at Minisatellite Loci in Sporadic Human Colorectal and Gastric Cancers—Possible Mechanistic Differences from Microsatellite Instability in Cancer Cells

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