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  • Hyperinsulinemia and insulin resistance in Wrn null mice fed a diabetogenic diet. 18295300

    Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by mutations in the Werner (Wrn) gene. WS patients have increased incidence of a number of chronic conditions including insulin resistance and type 2 diabetes. Since ingestion of foods that are high in fat and sugar is associated with increased incidence of diabetes, we examined if Wrn mutations might affect metabolic response to a diabetogenic diet. Four-month-old mice with a null mutation for the Wrn gene were fed a diet consisting of 36% fat (lard), 33% table sugar, and 20% protein plus balanced vitamins and minerals. Wrn null mice had significantly increased body weights, increased serum insulin levels, impaired glucose tolerance, and insulin resistance during 4 months of eating the diabetogenic diet. Diffuse fatty infiltration of the liver and pancreatic islet hyperplasia was characteristic morphological features. These observations suggest that Wrn null mice have impaired glucose homeostasis and fat metabolism, and may be a useful model to investigate metabolic conditions associated with aging.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    Mehrere
    Produktbezeichnung:
    Mehrere

  • Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway. 16264192

    Werner Syndrome (WS) is characterized by premature aging, genomic instability, and cancer. The combined impact of WRN helicase deficiency and limiting telomere reserves is central to disease pathogenesis. Here, we report that cells doubly deficient for telomerase and WRN helicase show chromosomal aberrations and elevated recombination rates between telomeres of sister chromatids. Somatic reconstitution of WRN function, but not a WRN helicase-deficient mutant, abolished telomere sister chromatid exchange (T-SCE), indicating that WRN normally represses T-SCEs. Elevated T-SCE was associated with greater immortalization potential and resultant tumors maintained telomeres via the alternative lengthening of telomere (ALT) pathway. We propose that the increased incidence of chromosomal instability and cancer in WS relates in part to aberrant recombinations between sister chromatids at telomeres, which facilitates the activation of ALT and engenders cancer-relevant chromosomal aberrations and tumor formation.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    Mehrere
    Produktbezeichnung:
    Mehrere

  • ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence. 23933816

    Werner syndrome (WS) results from dysfunction of the WRN protein, and is associated with premature aging and early death. Here we report that loss of WRN function elicits accumulation of the Yes-associated protein (YAP protein), a major effector of the Hippo tumor suppressor pathway, both experimentally and in WS-derived fibroblasts. YAP upregulation correlates with slower cell proliferation and accelerated senescence, which are partially mediated by the formation of a complex between YAP and the PML protein, whose activity promotes p53 activation. The ATM kinase is necessary for YAP and PML accumulation in WRN-depleted cells. Notably, the depletion of either YAP or PML partially impairs the induction of senescence following WRN loss. Altogether, our findings reveal that loss of WRN activity triggers the activation of an ATM-YAP-PML-p53 axis, thereby accelerating cellular senescence. The latter has features of SASP (senescence-associated secretory phenotype), whose protumorigenic properties are potentiated by YAP, PML and p53 depletion.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    06-866
    Produktbezeichnung:
    Anti-acetyl-Histone H4 Antibody

  • Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease. 19666486

    Hirschsprung disease (HSCR) is a common, multigenic neurocristopathy characterized by incomplete innervation along a variable length of the gut. The pivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR also presents in various syndromes, including Shah-Waardenburg syndrome (WS), Down (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays. Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease. We also demonstrate that these genes interact genetically in vivo to modulate gut innervation, and that this interaction likely occurs through complementary, yet independent, pathways that converge on the same biological process.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    AB5535
    Produktbezeichnung:
    Anti-Sox9 Antibody

  • Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways. 26755828

    Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ∼28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams-Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at chromosome 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    17-371
    Produktbezeichnung:
    EZ-ChIP™

  • Suckling-induced Fos activation and melanin-concentrating hormone immunoreactivity during late lactation. 26874026

    Melanin-concentrating hormone (MCH) is implicated in the control of food intake, body weight regulation and energy homeostasis. Lactation is an important physiological model to study the hypothalamic integration of peripheral sensory signals, such as suckling stimuli and those related to energy balance. MCH can be detected in the medial preoptic area (MPOA), especially around the 19th day of lactation, when this hormone is described as displaying a peak synthesis followed by a decrease after weaning. The physiological significance of this phenomenon is unclear. Therefore, we aimed to investigate hypothalamic changes associated to sensory stimulation by the litter, in special its influence over MCH synthesis.Female Wistar rats (n=56) were euthanized everyday from lactation days 15-21, with or without suckling stimulus (WS and NS groups, respectively). MCH and Fos immunoreactivity were evaluated in the MPOA and lateral and incerto-hypothalamic areas (LHA and IHy).Suckling stimulus induced Fos synthesis in all regions studied. An increase on the number of suckling-induced Fos-ir neurons could be detected in the LHA after the 18th day. Conversely, the amount of MCH decreased in the MPOA from days 15-21, independent of suckling stimulation. No colocalization between MCH and Fos could be detected in any region analyzed.Suckling stimulus is capable of stimulating hypothalamic regions not linked to maternal behavior, possibly to mediate energy balance aspects of lactation. Although dams are hyperphagic before weaning, this behavioral change does not appear to be mediated by MCH.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    ABE457
    Produktbezeichnung:
    Anti-c-Fos Antibody

  • Liver fatty acid-binding protein binds monoacylglycerol in vitro and in mouse liver cytosol. 23658011

    Liver fatty acid-binding protein (LFABP; FABP1) is expressed both in liver and intestinal mucosa. Mice null for LFABP were recently shown to have altered metabolism of not only fatty acids but also monoacylglycerol, the two major products of dietary triacylglycerol hydrolysis (Lagakos, W. S., Gajda, A. M., Agellon, L., Binas, B., Choi, V., Mandap, B., Russnak, T., Zhou, Y. X., and Storch, J. (2011) Am. J. Physiol. Gastrointest. Liver Physiol. 300, G803-G814). Nevertheless, the binding and transport of monoacylglycerol (MG) by LFABP are uncertain, with conflicting reports in the literature as to whether this single chain amphiphile is in fact bound by LFABP. In the present studies, gel filtration chromatography of liver cytosol from LFABP(-/-) mice shows the absence of the low molecular weight peak of radiolabeled monoolein present in the fractions that contain LFABP in cytosol from wild type mice, indicating that LFABP binds sn-2 MG in vivo. Furthermore, solution-state NMR spectroscopy demonstrates two molecules of sn-2 monoolein bound in the LFABP binding pocket in positions similar to those found for oleate binding. Equilibrium binding affinities are ∼2-fold lower for MG compared with fatty acid. Finally, kinetic studies examining the transfer of a fluorescent MG analog show that the rate of transfer of MG is 7-fold faster from LFABP to phospholipid membranes than from membranes to membranes and occurs by an aqueous diffusion mechanism. These results provide strong support for monoacylglycerol as a physiological ligand for LFABP and further suggest that LFABP functions in the efficient intracellular transport of MG.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    ABS538
    Produktbezeichnung:
    Anti-FABP1 Antibody

  • Principal glycopeptide of the tetrodotoxin/saxitoxin binding protein from Electrophorus electricus: isolation and partial chemical and physical characterization. 6186277

    Preparations of the tetrodotoxin (TTX) and saxitoxin binding protein isolated from the electroplax of Electrophorus electricus are of high specific activity (greater than or equal to 2000 pmol of TTX binding sites/mg of protein) and appear to be homogeneous in that they contain only the large polypeptide previously identified to make up part of the voltage-sensitive sodium channel [Agnew, W. S., Moore, A. C., Levinson, S. R., & Raftery, M. S. (1980) Biochem. Biophys. Res. Commun. 92, 860-866]. This permits the inference that the TTX binding site, thought to be associated with the mouth of the ion channel, is located on this peptide. This peptide presumably corresponds to the large peptide, designated the alpha-peptide subunit, of the synaptosomal sodium channel [Hartshorne, R. P., & Catterall, W. A. (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 4620-4624]. No convincing evidence for lower molecular weight peptides has yet been found for the electroplax protein. A rapid and convenient method is described for preparation of milligram quantities of the pure, sodium dodecyl sulfate (NaDodSO4) denatured form of the peptide, and its amino acid and carbohydrate compositions are reported. The peptide behaved anomalously on NaDodSO4-polyacrylamide gels. It was demonstrated that the molecular weight cannot be accurately quantified by this method but that the true value likely exceeds the value of 260 000 reported previously. The denatured peptide displayed an electrophoretic microheterogeneity which may be ascribed to variations in bulky carbohydrate substituents and an extremely high free mobility which is inferred to result from binding of unusually large amounts of NaDodSO4.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    06-811
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