Insulin-Degrading Enzyme: Stable Expression of the Human Complementary DNA, Characterization of its Protein Product, and Chromosomal Mapping of the Human and Mouse Genes

Affholter, Joseph A.; Hsieh, Chih‐Lin; Francke, Uta; Roth, Richard A.

doi:10.1210/mend-4-8-1125

Cited by 65 publications

(56 citation statements)

References 27 publications

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“…The inhibitor Cpp-Ala-Ala-Phe-pAB, which is a non-permeable specific inhibitor of MP24.15, had a partial inhibitory effect on the A␤ peptide degradation, while Zincov had only a slight inhibitory effect. 1,10-Phenanthroline (4 mM) and insulin (1-10 M) which are both known to completely inhibit the IDE (29,38,39), had low inhibitory effects on A␤ degradation (Table I). successful, indicating that serum is needed in addition to MP24.15 for A␤ degradation to occur (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Metalloendopeptidase EC 3.4.24.15 Is Necessary for Alzheimer's Amyloid-β Peptide Degradation

Yamin

Malgeri

Sloane

et al. 1999

Journal of Biological Chemistry

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We have investigated the functional relationship between metalloendopeptidase EC 3.4.24.15 (MP24.15) and the amyloid precursor protein involved in Alzheimer's disease (AD) and discovered that the enzyme promotes A␤ degradation. We show here that conditioned medium (CM) of MP24.15 antisense-transfected SKNMC neuroblastoma has significantly higher levels of A␤. Furthermore, synthetic-A␤ degradation was increased or decreased following incubation with CM of sense or antisense-transfected cells, respectively. Soluble A␤1-42 was degraded more slowly than soluble A␤1-40, while aggregated A␤1-42 showed almost no degradation. Alzheimer's disease (AD)1 is a progressive neurodegenerative disorder and the most common form of dementia in the elderly (1). Evidence indicates that accumulation of amyloid-␤ (A␤) deposits in senile plaques and in cerebrovasculature is associated with the pathophysiology of AD (2). The A␤ peptide is composed of 40 -42 amino acids (3). The events leading to its formation from the transmembrane amyloid precursor protein (APP) involve proteolytic cleavage by enzymes that have been termed: 1) ␤-secretase, which cleaves at the amino terminus of A␤, and 2) ␥-secretase, which cleaves at the carboxyl terminus. In the senile plaques A␤ is associated with a number of proteins, including ␣ 1 -antichymotrypsin (ACT) (4), which is a serine proteinase inhibitor of the serpin family as well as an acute-phase protein (5). Thus, we hypothesized 10 years ago that ACT may play a role in APP processing (4, 6).Soluble A␤ peptide can be detected in the conditioned media of a variety of cultured mammalian cells in vitro (7-9), as well as in serum and cerebrospinal fluid in vivo (10). The majority of secreted A␤ is 40 amino acids in length (A␤1-40), but approximately 10% of all A␤ is 42 amino acids in length (A␤1-42) (11). Little is known about how secreted A␤ is degraded and cleared from the extracellular milieu. The excessive cerebral accumulation of A␤ that occurs in AD could be explained in part by a decreased ability of the brain to degrade and clear A␤. If neural cells can be shown to release specific A␤-degrading proteinases, changes in the activity of such proteinases and/or their upregulation could represent a therapeutic approach to AD.We have explored the role of the metalloendopeptidase MP24.15 in the degradation of A␤. MP24.15 is a thiol-dependent enzyme that was purified to homogeneity from AD brain as a candidate ␤-secretase (12). McDermot et al. (13) also identified a partially purified MP24.15 as a potential ␤-secretase using synthetic peptide substrates. In vitro, MP24.15 has been shown to be involved in the inactivation of a number of neuropeptides, including somatostatin, bradykinin, substance P, and neurotensin (14 -16). The cDNA coding for MP24.15 was subsequently cloned from a human brain library (17,18). In an attempt to further examine the ␤-secretase properties of MP24.15 under physiologic conditions, we transfected human neuroblastoma cells with MP24.15 cDNA in the sense and antisense directi...

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Section: Resultsmentioning

confidence: 99%

Metalloendopeptidase EC 3.4.24.15 Is Necessary for Alzheimer's Amyloid-β Peptide Degradation

Yamin

Malgeri

Sloane

et al. 1999

Journal of Biological Chemistry

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“…This gene was con®rmed to map to the Lvis1 locus by genetic mapping and was designated msec15 (Figure 2b,c). (White et al, 1998) 19 (Aholter et al, 1990) 19 (this study) 19 (this study) 19 (this study) a Genbank accession number of human or mouse ESTs used in this study. No mouse ESTs were identi®ed by Blast searches using UniGene EST assemblies, as the assembled UniGene sequences represent only the 3' UTR of IDE, for which human and mouse sequence is not available.…”

Section: Gene Identi®cationmentioning

confidence: 99%

“…No mouse ESTs were identi®ed by Blast searches using UniGene EST assemblies, as the assembled UniGene sequences represent only the 3' UTR of IDE, for which human and mouse sequence is not available. The mouse homolog of rat IDE has been cloned (Aholter et al, 1990), and mouse ESTs representing the coding region of IDE are present in the EST databases, but were not used in this study Figure 4 Expression of Hex, mEg5, and msec15 in AKXD-18 Bcell leukemias. DNA probes containing Hex (a), mEg5 (b), and msec15 (c) coding sequences were hybridized sequentially to a ®lter containing 20 mg total spleen RNA from AKXD-18 leukemic animals.…”

Section: Gene Identi®cationmentioning

confidence: 99%

Activation of Hex and mEg5 by retroviral insertion may contribute to mouse B-cell leukemia

Hansen

Justice

1999

Oncogene

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AKXD recombinant inbred mice develop a variety of leukemias and lymphomas due to retrovirally mediated insertional activation of cellular proto-oncogenes. We describe a new retroviral insertion site that is the most frequent genetic alteration in AKXD B-cell leukemias. Multiple genes¯ank the site of viral insertion, but the expression of just two, Hex and mEg5, is signi®cantly upregulated. Hex is a divergent homeobox gene that is transiently expressed in many hematopoietic lineages, suggesting an involvement in cellular dierentiation. mEg5 is a member of the bim-C subfamily of kinesin related proteins that are necessary for spindle formation and stabilization during mitosis. Our data provide the ®rst genetic evidence for the activation of these genes in leukemia, and suggest that unscheduled expression of Hex and mEg5 contributes to the development of B-cell leukemia. In addition, this work highlights the use of genomic approaches for the study of position eect mutations.

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“…IDE is the major enzyme responsible for insulin proteolysis in vitro (5) and shares structural and functional homology with bacterial protease III, which may function in the termination of the insulin response (6,7). In mice, IDE hypofunction induced by IDE gene disruption leads to hyperinsulinemia (8).…”

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confidence: 99%

Quantitative Trait Loci Near the Insulin-Degrading Enzyme (IDE) Gene Contribute to Variation in Plasma Insulin Levels

Efendić

Nordman

et al. 2004

Diabetes

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Insulin-degrading enzyme (IDE) plays a principal role in the proteolysis of several peptides in addition to insulin and is encoded by IDE, which resides in a region of chromosome 10q that is linked to type 2 diabetes. Two recent studies presented genetic association data on IDE and type 2 diabetes (one positive and the other negative), but neither explored the fundamental question of whether polymorphism in IDE has a measurable influence on insulin levels in human populations. To address this possibility, 14 single nucleotide polymorphisms (SNPs) from a linkage disequilibrium block encompassing IDE have been genotyped in a sample of 321 impaired glucose tolerant and 403 nondiabetic control subjects. Analyses based on haplotypic genotypes (diplotypes), constructed with SNPs that differentiate common extant haplotypes extending across IDE, provided compelling evidence of association with fasting insulin levels (P ‫؍‬ 0.0009), 2-h insulin levels (P ‫؍‬ 0.0027), homeostasis model assessment of insulin resistance (P ‫؍‬ 0.0001), and BMI (P ‫؍‬ 0.0067), with effects exclusively evident in men. The strongest evidence for an effect of a single marker was obtained for rs2251101 (located near the 3 untranslated region of IDE) on 2-h insulin levels (P ‫؍‬ 0.000023). Diplotype analyses, however, suggest the presence of multiple interacting traitmodifying sequences in the region. Results indicate that polymorphism in/near IDE contributes to a large proportion of variance in plasma insulin levels and correlated traits, but questions of sex specificity and allelic heterogeneity will need to be taken into consideration as the molecular basis of the observed phenotypic effects unfolds. Diabetes 53:2137-2142, 2004 T he gene encoding insulin-degrading enzyme (IDE) is located on chromosome 10q23-q24, within a region linked to type 2 diabetes and related quantitative traits (1-4). IDE is the major enzyme responsible for insulin proteolysis in vitro (5) and shares structural and functional homology with bacterial protease III, which may function in the termination of the insulin response (6,7). In mice, IDE hypofunction induced by IDE gene disruption leads to hyperinsulinemia (8). Furthermore, IDE activity in the diabetic Goto-Kakizaki (GK) rat is reduced by ϳ30%, where polymorphism in IDE is likely to be the main contributing factor (9). Congruence of positional and functional data indicates that sequence variation in IDE may play a role in modifying insulin metabolism in human populations. Two recent genetic association studies investigated the IDE region in relation to type 2 diabetes. One produced significant evidence for effects on both type 2 diabetes and plasma glucose levels (10), whereas the other explored only case-control models and obtained no evidence of association (11). Neither of these studies, however, attempted to directly relate IDE variants to measures of insulin metabolism.To evaluate the potential influence of genetic variation in IDE on insulin levels and correlated quantitative traits, a haplotype-tagging stra...

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Insulin-Degrading Enzyme: Stable Expression of the Human Complementary DNA, Characterization of its Protein Product, and Chromosomal Mapping of the Human and Mouse Genes

Cited by 65 publications

References 27 publications

Metalloendopeptidase EC 3.4.24.15 Is Necessary for Alzheimer's Amyloid-β Peptide Degradation

Metalloendopeptidase EC 3.4.24.15 Is Necessary for Alzheimer's Amyloid-β Peptide Degradation

Activation of Hex and mEg5 by retroviral insertion may contribute to mouse B-cell leukemia

Quantitative Trait Loci Near the Insulin-Degrading Enzyme (IDE) Gene Contribute to Variation in Plasma Insulin Levels

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