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  • JDP2 (Jun Dimerization Protein 2)-deficient mouse embryonic fibroblasts are resistant to replicative senescence. 19233846

    JDP2 (Jun dimerization protein 2, an AP-1 transcription factor) is involved in the regulation of the differentiation and proliferation of cells. We report here that JDP2-deficient mouse embryonic fibroblasts (Jdp2(-/-) MEF) are resistant to replicative senescence. In the absence of JDP2, the level of expression of p16(Ink4a), which is known to rise as normal fibroblasts age, fell significantly when cells were cultured for more than 2 months. Conversely, the overexpression of JDP2 induced the expression of genes for p16(Ink4a) and p19(Arf). Moreover, at the promoter of the gene for p16(Ink4a) in Jdp2(-/-) MEF, the extent of methylation of lysine 27 of histone H3 (H3K27), which is important for gene silencing, increased. Polycomb-repressive complexes (PRC-1 and PRC-2), which are responsible for histone methylation, bound efficiently to the promoter to repress the expression of the gene for p16(Ink4a). As a result, JDP2-deficient MEF became resistant to replicative senescence. Our results indicate that JDP2 is involved in the signaling pathway for senescence via epigenetic regulation of the expression of the gene for p16(Ink4a).
    Document Type:
    Reference
    Product Catalog Number:
    05-637
    Product Catalog Name:
    Anti-Bmi-1 Antibody, clone F6

  • Vein tissue expression of matrix metalloproteinase as biomarker for hemodialysis arteriovenous fistula maturation. 20724289

    Failure of arteriovenous fistula (AVF) maturation is attributed to impaired vein remodeling. The purpose of this study is to identify whether vein matrix metalloproteinase (MMP) expression and activity is associated with AVF maturation. Patients with renal insufficiency undergoing surgery had their vein segments harvested and snap-frozen at time of AVF construction. Expression of MMP-2, MMP-9, membrane type-1 MMP (MT1-MMP), tissue inhibitor of metallopreoteinases type 2 (TIMP-2), and TIMP-4 were measured using zymography and Western blotting techniques. Of 14 patients enrolled, 9 had successful maturation and 5 had failure of AVF maturation. Significantly higher levels of MT1-MMP (an MMP-2 activator; P = .01), TIMP-2 (an MMP-2 inhibitor; P = .03), MMP-2 latent (P = .02), and MMP-2 total (P = .03) were associated with AVF maturation. There was a trend toward higher levels of TIMP-4 in the successful group (P = .18). These data demonstrate a positive relationship between MMP-2 expression in veins and AVF maturation. MMP-2 could serve as a potential preoperative marker to predict maturation.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Caloric Restriction Reverses Hepatic Insulin Resistance and Steatosis in Rats with Low Aerobic Capacity. 20861239

    Rats selectively bred for low aerobic running capacity exhibit the metabolic syndrome, including hyperinsulinemia, insulin resistance, visceral obesity, and dyslipidemia. They also exhibit features of nonalcoholic steatohepatitis, including chicken-wire fibrosis, inflammation, and oxidative stress. Hyperinsulinemia in these rats is associated with impaired hepatic insulin clearance. The current studies aimed to determine whether these metabolic abnormalities could be reversed by caloric restriction (CR). CR by 30% over a period of 2-3 months improved insulin clearance in parallel to inducing the protein content and activation of the carcinoembryonic antigen-related cell adhesion molecule 1, a main player in hepatic insulin extraction. It also reduced glucose and insulin intolerance and serum and tissue (liver and muscle) triglyceride levels. Additionally, CR reversed inflammation, oxidative stress, and fibrosis in liver. The data support a significant role of CR in the normalization of insulin and lipid metabolism in liver.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • GFAP-Cre-mediated activation of oncogenic K-ras results in expansion of the subventricular zone and infiltrating glioma. 19435821

    A subset of neoplastic cells within human high-grade gliomas has features associated with stem cells. These cells may sustain glioma growth, and their stem-like properties may confer resistance to standard glioma treatments. Whether glioma stem cells derive from indigenous neural stem cells (NSC), or from tumor cells that have reacquired stem cell-like properties, is unknown. However, signaling pathways that are tightly regulated and central to NSC biology, including the Ras/Raf/Erk pathway, are hyperactive and pathogenic in gliomagenesis. Furthermore, data in animal models suggests that, in some cases, tumors are initiated in the subventricular zone (SVZ), a stem/progenitor cell niche in the mature brain. We activated oncogenic K-ras in mouse glioneuronal precursor cells and adult SVZ cells using GFAP-Cre. GFAP-Cre+/K-ras(G12D) mice showed a marked expansion of glial fibriallary acidic protein (GFAP)- and TUJ1-expressing cell populations in the SVZ. In addition, mice developed intermediate grade, infiltrating glioma with 100% penetrance. Tumors were consistently located in the amygdalohippocampal region and nearby cortex, often in association with the lateral ventricle and expanded SVZ. Tumor cells expressed markers associated with neural progenitor cells, including Olig2, Bmi-1, and PDGFR-alpha. These data suggest that infiltrating tumor cells may arise from NSC transformed by activation of oncogenic K-ras in vivo.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity. 18650381

    Polycomb-group (PcG) genes encode multimeric nuclear protein complexes, PcG complex 1 and 2. PcG complex 2 was proved to induce transcription repression and to further methylate histone H3 at lysine-27 (H3K27). Subsequently PcG complex 1 is recruited through recognition of methylated H3K27 and maintains the transcription silencing by mediating monoubiquitination of histone H2A at lysine-119. Genetic evidence demonstrated a crucial role for PcG complex 1 in stem cells, and Bmi1, a member of PcG complex 1, was shown to sustain adult stem cells through direct repression of the INK4a locus encoding cyclin-dependent kinase inhibitor, p16CKI, and p19ARF. The molecular functions of PcG complex 1, however, remain insufficiently understood. In our study, deficiency of Rae28, a member of PcG complex 1, was found to impair ubiquitin-proteasome-mediated degradation of Geminin, an inhibitor of DNA replication licensing factor Cdt1, and to increase protein stability. The resultant accumulation of Geminin, based on evidence from retroviral transduction experiments, presumably eliminated hematopoietic stem cell activity in Rae28-deficient mice. Rae28 mediates recruiting Scmh1, which provides PcG complex 1 an interaction domain for Geminin. Moreover, PcG complex 1 acts as the E3 ubiquitin ligase for Geminin, as we demonstrated in vivo as well as in vitro by using purified recombinant PcG complex 1 reconstituted in insect cells. Our findings suggest that PcG complex 1 supports the activity of hematopoietic stem cells, in which high-level Geminin expression induces quiescence securing genome stability, by enhancing cycling capability and hematopoietic activity through direct regulation of Geminin.
    Document Type:
    Reference
    Product Catalog Number:
    05-637
    Product Catalog Name:
    Anti-Bmi-1 Antibody, clone F6

  • A novel zinc finger protein Zfp277 mediates transcriptional repression of the Ink4a/arf locus through polycomb repressive complex 1. 20808772

    Polycomb group (PcG) proteins play a crucial role in cellular senescence as key transcriptional regulators of the Ink4a/Arf tumor suppressor gene locus. However, how PcG complexes target and contribute to stable gene silencing of the Ink4a/Arf locus remains little understood.We examined the function of Zinc finger domain-containing protein 277 (Zfp277), a novel zinc finger protein that interacts with the PcG protein Bmi1. Zfp277 binds to the Ink4a/Arf locus in a Bmi1-independent manner and interacts with polycomb repressor complex (PRC) 1 through direct interaction with Bmi1. Loss of Zfp277 in mouse embryonic fibroblasts (MEFs) caused dissociation of PcG proteins from the Ink4a/Arf locus, resulting in premature senescence associated with derepressed p16(Ink4a) and p19(Arf) expression. Levels of both Zfp277 and PcG proteins inversely correlated with those of reactive oxygen species (ROS) in senescing MEFs, but the treatment of Zfp277(-/-) MEFs with an antioxidant restored the binding of PRC2 but not PRC1 to the Ink4a/Arf locus. Notably, forced expression of Bmi1 in Zfp277(-/-) MEFs did not restore the binding of Bmi1 to the Ink4a/Arf locus and failed to bypass cellular senescence. A Zfp277 mutant that could not bind Bmi1 did not rescue Zfp277(-/-) MEFs from premature senescence.Our findings implicate Zfp277 in the transcriptional regulation of the Ink4a/Arf locus and suggest that the interaction of Zfp277 with Bmi1 is essential for the recruitment of PRC1 to the Ink4a/Arf locus. Our findings also highlight dynamic regulation of both Zfp277 and PcG proteins by the oxidative stress pathways.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • COA 105637

    Document Type:
    Certificate of Analysis
    Product Catalog Number:
    105637

  • MYCN and MYC regulate tumor proliferation and tumorigenesis directly through BMI1 in human neuroblastomas. 21856782

    The BMI1 gene is overexpressed in ≈ 90% of human neuroblastomas. However, little is known about the regulation of BMI1 expression. Using microarray and immunohistochemical analysis, we show that BMI1 expression correlated with MYCN levels in MYCN-amplified human neuroblastomas, and with MYC levels in the MYCN-nonamplified group. We further demonstrated that BMI1 is a direct target gene of MYCN/MYC in 3 neuroblastoma cell lines: BE (2)-C, LAN1, and SH-SY5Y. Overexpression of MYCN or MYC transactivated the BMI1 promoter and up-regulated BMI1 gene expression. shRNA-mediated knockdown of MYCN or MYC decreased BMI1 gene expression. Chromatin immunoprecipitation and point-mutation assays revealed that both MYCN and MYC bind to the E-box within the BMI1 promoter. Overexpression of BMI1, MYCN, and MYC independently increased both cell proliferation and tumor growth. Conversely, specific inhibition of BMI1, MYCN, and MYC decreased tumor cell proliferation and tumor growth. Interestingly, BMI1 suppression in MYCN/MYC-overexpressing cells resulted in significantly greater inhibition compared to that in mock-transduced and parental cells. Our results indicate that MYCN and MYC regulate BMI1 gene expression at the transcriptional level and that dysregulation of the BMI1 gene mediated by MYCN or MYC overexpression, confers increased cell proliferation during neuroblastoma genesis and tumor progression.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple