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  • MYST family lysine acetyltransferase facilitates ataxia telangiectasia mutated (ATM) kinase-mediated DNA damage response in Toxoplasma gondii. 20159970

    The MYST family of lysine acetyltransferases (KATs) function in a wide variety of cellular operations, including gene regulation and the DNA damage response. Here we report the characterization of the second MYST family KAT in the protozoan parasite Toxoplasma gondii (TgMYST-B). Toxoplasma causes birth defects and is an opportunistic pathogen in the immunocompromised, the latter due to its ability to convert into a latent cyst (bradyzoite). We demonstrate that TgMYST-B can gain access to the parasite nucleus and acetylate histones. Overexpression of recombinant, tagged TgMYST-B reduces growth rate in vitro and confers protection from a DNA-alkylating agent. Expression of mutant TgMYST-B produced no growth defect and failed to protect against DNA damage. We demonstrate that cells overexpressing TgMYST-B have increased levels of ataxia telangiectasia mutated (ATM) kinase and phosphorylated H2AX and that TgMYST-B localizes to the ATM kinase gene. Pharmacological inhibitors of ATM kinase or KATs reverse the slow growth phenotype seen in parasites overexpressing TgMYST-B. These studies are the first to show that a MYST KAT contributes to ATM kinase gene expression, further illuminating the mechanism of how ATM kinase is up-regulated to respond to DNA damage.
    Document Type:
    Reference
    Product Catalog Number:
    05-636
    Product Catalog Name:
    Anti-phospho-Histone H2A.X (Ser139) Antibody, clone JBW301

  • Numb family proteins are essential for cardiac morphogenesis and progenitor differentiation. 24335256

    Numb family proteins (NFPs), including Numb and numb-like (Numbl), are cell fate determinants for multiple progenitor cell types. Their functions in cardiac progenitor differentiation and cardiac morphogenesis are unknown. To avoid early embryonic lethality and study NFP function in later cardiac development, Numb and Numbl were deleted specifically in heart to generate myocardial double-knockout (MDKO) mice. MDKOs were embryonic lethal and displayed a variety of defects in cardiac progenitor differentiation, cardiomyocyte proliferation, outflow tract (OFT) and atrioventricular septation, and OFT alignment. By ablating NFPs in different cardiac populations followed by lineage tracing, we determined that NFPs in the second heart field (SHF) are required for OFT and atrioventricular septation and OFT alignment. MDKOs displayed an SHF progenitor cell differentiation defect, as revealed by a variety of methods including mRNA deep sequencing. Numb regulated cardiac progenitor cell differentiation in an endocytosis-dependent manner. Studies including the use of a transgenic Notch reporter line showed that Notch signaling was upregulated in the MDKO. Suppression of Notch1 signaling in MDKOs rescued defects in p57 expression, proliferation and trabecular thickness. Further studies showed that Numb inhibits Notch1 signaling by promoting the degradation of the Notch1 intracellular domain in cardiomyocytes. This study reveals that NFPs regulate trabecular thickness by inhibiting Notch1 signaling, control cardiac morphogenesis in a Notch1-independent manner, and regulate cardiac progenitor cell differentiation in an endocytosis-dependent manner. The function of NFPs in cardiac progenitor differentiation and cardiac morphogenesis suggests that NFPs might be potential therapeutic candidates for cardiac regeneration and congenital heart diseases.
    Document Type:
    Reference
    Product Catalog Number:
    AB756P
    Product Catalog Name:
    Anti-Collagen Antibody, Type IV

  • A novel family of RGD-containing disintegrins (Tablysin-15) from the salivary gland of the horsefly Tabanus yao targets αIIbβ3 or αVβ3 and inhibits platelet aggregation a ... 21475772

    A novel family of RGD-containing molecules (Tablysin-15) has been molecularly characterised from the salivary gland of the haematophagous horsefly Tabanus yao. Tablysin-15 does not share primary sequence homology to any disintegrin discovered so far, and displays an RGD motif in the N-terminus of the molecule. It is also distinct from disintegrins from Viperidae since its mature form is not released from a metalloproteinase precursor. Tablysin-15 exhibits high affinity binding for platelet αIIbβ3 and endothelial cell αVβ3 integrins, but not for α5β1 or α2β1. Accordingly, it blocks endothelial cell adhesion to vitronectin (IC50 ~1 nM) and marginally to fibronectin (IC50 ~1 μM), but not to collagen. It also inhibits fibroblast growth factor (FGF)-induced endothelial cell proliferation, and attenuates tube formation in vitro. In platelets, Tablysin-15 inhibits aggregation induced by collagen, ADP and convulxin, and prevents static platelet adhesion to immobilised fibrinogen. In addition, solid-phase assays and flow cytometry demonstrates that αIIbβ3 binds to Tablysin-15. Moreover, immobilised Tablysin-15 supports platelet adhesion by a mechanism which was blocked by anti-integrin αIIbβ3 monoclonal antibody (e.g. abciximab) or by EDTA. Furthermore, Tablysin-15 dose-dependently attenuates thrombus formation to collagen under flow. Consistent with these findings, Tablysin-15 displays antithrombotic properties in vivo suggesting that it is a useful tool to block αIIbβ3, or as a prototype to develop antithrombotics. The RGD motif in the unique sequence of Tablysin-15 represents a novel template for studying the structure-function relationship of the disintegrin family of inhibitors.
    Document Type:
    Reference
    Product Catalog Number:
    CBL479
    Product Catalog Name:
    Anti-Integrin β3 Antibody, clone PM6/13

  • A src family kinase inhibitor improves survival in experimental acute liver failure associated with elevated cerebral and circulating vascular endothelial growth factor l ... 21745297

    Background and aims: Acute liver failure (ALF) is frequently complicated by cerebral oedema, systemic inflammation and multiorgan dysfunction. Vascular endothelial growth factor (VEGF) may stimulate liver regeneration but it can also be pro-inflammatory, activating endothelial cells and increasing permeability, actions mediated through Src kinase signalling. We therefore examined whether a Src inhibitor could have therapeutic potential in ALF. Methods: Murine ALF was induced with azoxymethane. Liver pathology was graded by a blinded examiner and apoptosis quantified by immunohistochemistry. Cerebral VEGF expression was imaged using VEGF-green fluorescent protein transgenic mice. Circulating and macrophage-secreted VEGF levels were measured. Experimental animals received a Src inhibitor or vehicle controls. Results: VEGF was undetectable in normal plasma but reached a mean of 835 pg/ml at grade III encephalopathy (P<0.001). Ammonia, lipopolysaccharide and interferon-gamma acted synergistically to enhance VEGF secretion by macrophages. Production of VEGF by cerebral cortical astrocytes increased with disease progression. Late treatment with inhibitors of Src or VEGF did not improve liver histology, encephalopathy or survival. However, early use of a Src kinase inhibitor significantly reduced hepatic injury, delayed encephalopathy and allowed 25% of mice to survive an otherwise lethal insult. Conclusion: Systemic and cerebral VEGF levels are significantly elevated during experimental ALF and may be exacerbated by hyperammonemia and macrophage activation. Early use of a Src inhibitor reduced hepatocellular injury and enabled survival, indicating such agents may have some promise in the treatment of ALF.© 2011 John Wiley & Sons A/S.
    Document Type:
    Reference
    Product Catalog Number:
    S7111
    Product Catalog Name:
    ApopTag® Plus In Situ Apoptosis Fluorescein Detection Kit

  • A family of metabotropic glutamate receptors. 1309649

    Three cDNA clones, mGluR2, mGluR3, and mGluR4, were isolated from a rat brain cDNA library by cross-hybridization with the cDNA for a metabotropic glutamate receptor (mGluR1). The cloned receptors show considerable sequence similarity with mGluR1 and possess a large extracellular domain preceding the seven putative membrane-spanning segments. mGluR2 is expressed in some particular neuronal cells different from those expressing mGluR1 and mediates an efficient inhibition of forskolin-stimulated cAMP formation in cDNA-transfected cells. The mGluRs thus form a novel family of G protein-coupled receptors that differ in their signal transduction and expression patterns.
    Document Type:
    Reference
    Product Catalog Number:
    AB1553
    Product Catalog Name:
    Anti-Metabotropic Glutamate Receptor 2/3 Antibody

  • LIM family transcription factors regulate the subtype-specific morphogenesis of retinal horizontal cells at post-migratory stages. 19361492

    In the nervous system, transcription factor expression in progenitor and/or nascent neurons regulates cell type specification. Although the functions of these transcription factors at early stages are well established, whether or not they are required during late developmental periods remains an open question. To address this issue, we conditionally manipulated gene expression using a recently developed transposon-mediated gene transfer system combined with in ovo electroporation. In chicken retinas, horizontal cells are classified into three subtypes according to their characteristic neuronal morphology. Two LIM family transcription factors, Lim1 and Isl1, begin to be expressed in a distinct subset of nascent retinal neurons, which results in complementary expression of these genes in mature retinas in type I and type II/III horizontal cells, respectively. Overexpression of Isl1 in post-migratory horizontal cells represses endogenous Lim1 expression and increases the number of neurons with a dendritic morphology characteristic of type II horizontal cells, which normally express Isl1. Inhibition of Lim1 function by expression of a dominant negative form Lim1 perturbs axonal morphogenesis of type I horizontal cells. Therefore, we propose that LIM family transcription factors are required for subtype-specific morphogenesis of horizontal cells at later stages of retinal development.
    Document Type:
    Reference
    Product Catalog Number:
    AB5475
    Product Catalog Name:
    Anti-Prox 1 Antibody

  • A family of human cdc2-related protein kinases. 1639063

    The p34cdc2 protein kinase is known to regulate important transitions in the eukaryotic cell cycle. We have identified 10 human protein kinases based on their structural relation to p34cdc2. Seven of these kinases are novel and the products of five share greater than 50% amino acid sequence identity with p34cdc2. The seven novel genes are broadly expressed in human cell lines and tissues with each displaying some cell type or tissue specificity. The cdk3 gene, like cdc2 and cdk2, can complement cdc28 mutants of Saccharomyces cerevisiae, suggesting that all three of these protein kinases can play roles in the regulation of the mammalian cell cycle. The identification of a large family of cdc2-related kinases opens the possibility of combinatorial regulation of the cell cycle together with the emerging large family of cyclins.
    Document Type:
    Reference
    Product Catalog Number:
    14-132

  • The B56 family of protein phosphatase 2A (PP2A) regulatory subunits encodes differentiation-induced phosphoproteins that target PP2A to both nucleus and cytoplasm. 8703017

    Protein phosphatase 2A is a heterotrimeric protein serine/threonine phosphatase consisting of a 36-kDa catalytic C subunit, a 65-kDa structural A subunit, and a variable regulatory B subunit. The B subunits determine the substrate specificity of the enzyme. There have been three families of cellular B subunits identified to date: B55, B56 (B'), and PR72/130. We have now cloned five genes encoding human B56 isoforms. Polypeptides encoded by all but one splice variant (B56gamma1) are phosphoproteins, as shown by mobility shift after treatment with alkaline phosphatase and metabolic labeling with [32P]phosphate. All labeled isoforms contain solely phosphoserine. Indirect immunofluorescence microscopy demonstrates distinct patterns of intracellular targeting by different B56 isoforms. Specifically, B56alpha, B56beta, and B56epsilon complexed with the protein phosphatase 2A A and C subunits localize to the cytoplasm, whereas B56delta, B56gamma1, and B56gamma3 are concentrated in the nucleus. Two isoforms (B56beta and B56delta) are highly expressed in adult brain; here we show that mRNA for these isoforms increases severalfold when neuroblastoma cell lines are induced to differentiate by retinoic acid treatment. These studies demonstrate an increasing diversity of regulatory mechanisms to control the activity of this key intracellular protein phosphatase and suggest distinct functions for isoforms targeted to different intracellular locations.
    Document Type:
    Reference
    Product Catalog Number:
    07-334

  • The EBNA3 family of Epstein-Barr virus nuclear proteins associates with the USP46/USP12 deubiquitination complexes to regulate lymphoblastoid cell line growth. 25855980

    The Epstein-Barr virus (EBV) nuclear proteins EBNA3A, EBNA3B, and EBNA3C interact with the cell DNA binding protein RBPJ and regulate cell and viral genes. Repression of the CDKN2A tumor suppressor gene products p16(INK4A) and p14(ARF) by EBNA3A and EBNA3C is critical for EBV mediated transformation of resting B lymphocytes into immortalized lymphoblastoid cell lines (LCLs). To define the composition of endogenous EBNA3 protein complexes, we generated lymphoblastoid cell lines (LCLs) expressing flag-HA tagged EBNA3A, EBNA3B, or EBNA3C and used tandem affinity purification to isolate each EBNA3 complex. Our results demonstrated that each EBNA3 protein forms a distinct complex with RBPJ. Mass-spectrometry revealed that the EBNA3A and EBNA3B complexes also contained the deubquitylation complex consisting of WDR48, WDR20, and USP46 (or its paralog USP12) and that EBNA3C complexes contained WDR48. Immunoprecipitation confirmed that EBNA3A, EBNA3B, and EBNA3C association with the USP46 complex. Using chromatin immunoprecipitation, we demonstrate that WDR48 and USP46 are recruited to the p14(ARF) promoter in an EBNA3C dependent manner. Mapping studies were consistent with WDR48 being the primary mediator of EBNA3 association with the DUB complex. By ChIP assay, WDR48 was recruited to the p14(ARF) promoter in an EBNA3C dependent manner. Importantly, WDR48 associated with EBNA3A and EBNA3C domains that are critical for LCL growth, suggesting a role for USP46/USP12 in EBV induced growth transformation.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple