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KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production.
Pabbisetty SK, Rabacal W, Maseda D, Cendron D, Collins PL, Hoek KL, Parekh VV, Aune TM, Sebzda E
(2014) Proc Natl Acad Sci U S A 111: 9579-84
MeSH Terms: Animals, Autoimmunity, Cell Differentiation, Chromatin Immunoprecipitation, DNA Primers, Flow Cytometry, Kruppel-Like Transcription Factors, Mice, Mice, Inbred C57BL, Mice, Transgenic, T-Lymphocytes, Regulatory
Show Abstract · Added July 24, 2014
Regulatory T cells (Tregs) are a specialized subset of CD4(+) T cells that maintain self-tolerance by functionally suppressing autoreactive lymphocytes. The Treg compartment is composed of thymus-derived Tregs (tTregs) and peripheral Tregs (pTregs) that are generated in secondary lymphoid organs after exposure to antigen and specific cytokines, such as TGF-β. With regard to this latter lineage, pTregs [and their ex vivo generated counterparts, induced Tregs (iTregs)] offer particular therapeutic potential because these cells can be raised against specific antigens to limit autoimmunity. We now report that transcription factor Krüppel-like factor 2 (KLF2) is necessary for the generation of iTregs but not tTregs. Moreover, drugs that limit KLF2 proteolysis during T-cell activation enhance iTreg development. To the authors' knowledge, this study identifies the first transcription factor to distinguish between i/pTreg and tTreg ontogeny and demonstrates that KLF2 is a therapeutic target for the production of regulatory T cells.
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3 Members
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11 MeSH Terms
Lymphatic function is required prenatally for lung inflation at birth.
Jakus Z, Gleghorn JP, Enis DR, Sen A, Chia S, Liu X, Rawnsley DR, Yang Y, Hess PR, Zou Z, Yang J, Guttentag SH, Nelson CM, Kahn ML
(2014) J Exp Med 211: 815-26
MeSH Terms: Animals, Animals, Newborn, Calcium-Binding Proteins, DNA Primers, Echocardiography, Embryo, Mammalian, Fetus, Immunohistochemistry, Lung, Lung Compliance, Lymphatic System, Lymphography, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Pulmonary Edema, Real-Time Polymerase Chain Reaction, Tumor Suppressor Proteins, Vascular Endothelial Growth Factor Receptor-3
Show Abstract · Added January 20, 2015
Mammals must inflate their lungs and breathe within minutes of birth to survive. A key regulator of neonatal lung inflation is pulmonary surfactant, a lipoprotein complex which increases lung compliance by reducing alveolar surface tension (Morgan, 1971). Whether other developmental processes also alter lung mechanics in preparation for birth is unknown. We identify prenatal lymphatic function as an unexpected requirement for neonatal lung inflation and respiration. Mice lacking lymphatic vessels, due either to loss of the lymphangiogenic factor CCBE1 or VEGFR3 function, appear cyanotic and die shortly after birth due to failure of lung inflation. Failure of lung inflation is not due to reduced surfactant levels or altered development of the lung but is associated with an elevated wet/dry ratio consistent with edema. Embryonic studies reveal active lymphatic function in the late gestation lung, and significantly reduced total lung compliance in late gestation embryos that lack lymphatics. These findings reveal that lymphatic vascular function plays a previously unrecognized mechanical role in the developing lung that prepares it for inflation at birth. They explain respiratory failure in infants with congenital pulmonary lymphangiectasia, and suggest that inadequate late gestation lymphatic function may also contribute to respiratory failure in premature infants.
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19 MeSH Terms
Pro32Pro33 mutations in the integrin β3 PSI domain result in αIIbβ3 priming and enhanced adhesion: reversal of the hypercoagulability phenotype by the Src inhibitor SKI-606.
Oliver KH, Jessen T, Crawford EL, Chung CY, Sutcliffe JS, Carneiro AM
(2014) Mol Pharmacol 85: 921-31
MeSH Terms: Amino Acid Sequence, Aniline Compounds, Animals, Base Sequence, Cell Adhesion, DNA Primers, Humans, Integrin beta3, Mice, Molecular Sequence Data, Mutation, Nitriles, Phenotype, Platelet Glycoprotein GPIIb-IIIa Complex, Polymerase Chain Reaction, Proline, Quinolines, Sequence Homology, Amino Acid, Thrombophilia, src-Family Kinases
Show Abstract · Added February 12, 2015
The plasma-membrane integrin αIIbβ3 (CD41/CD61, GPIIbIIIa) is a major functional receptor in platelets during clotting. A common isoform of integrin β3, Leu33Pro is associated with enhanced platelet function and increased risk for coronary thrombosis and stroke, although these findings remain controversial. To better understand the molecular mechanisms by which this sequence variation modifies platelet function, we produced transgenic knockin mice expressing a Pro32Pro33 integrin β3. Consistent with reports utilizing human platelets, we found significantly reduced bleeding and clotting times, as well as increased in vivo thrombosis, in Pro32Pro33 homozygous mice. These alterations paralleled increases in platelet attachment and spreading onto fibrinogen resulting from enhanced integrin αIIbβ3 function. Activation with protease-activated receptor 4- activating peptide, the main thrombin signaling receptor in mice, showed no significant difference in activation of Pro32Pro33 mice as compared with controls, suggesting that inside-out signaling remains intact. However, under unstimulated conditions, the Pro32Pro33 mutation led to elevated Src phosphorylation, facilitated by increased talin interactions with the β3 cytoplasmic domain, indicating that the αIIbβ3 intracellular domains are primed for activation while the ligand-binding domain remains unchanged. Acute dosing of animals with a Src inhibitor was sufficient to rescue the clotting phenotype in knockin mice to wild-type levels. Together, our data establish that the Pro32Pro33 structural alteration modifies the function of integrin αIIbβ3, priming the integrin for outside-in signaling, ultimately leading to hypercoagulability. Furthermore, our data may support a novel approach to antiplatelet therapy by Src inhibition where hemostasis is maintained while reducing risk for cardiovascular disease.
2 Communities
3 Members
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20 MeSH Terms
5-methylcytosine recognition by Arabidopsis thaliana DNA glycosylases DEMETER and DML3.
Brooks SC, Fischer RL, Huh JH, Eichman BF
(2014) Biochemistry 53: 2525-32
MeSH Terms: 5-Methylcytosine, Arabidopsis, Arabidopsis Proteins, Base Sequence, DNA Glycosylases, DNA Primers, Models, Molecular, Nuclear Proteins, Polymerase Chain Reaction, Substrate Specificity
Show Abstract · Added May 27, 2014
Methylation of cytosine to 5-methylcytosine (5mC) is important for gene expression, gene imprinting, X-chromosome inactivation, and transposon silencing. Active demethylation in animals is believed to proceed by DNA glycosylase removal of deaminated or oxidized 5mC. In plants, 5mC is removed from the genome directly by the DEMETER (DME) family of DNA glycosylases. Arabidopsis thaliana DME excises 5mC to activate expression of maternally imprinted genes. Although the related Repressor of Silencing 1 (ROS1) enzyme has been characterized, the molecular basis for 5mC recognition by DME has not been investigated. Here, we present a structure-function analysis of DME and the related DME-like 3 (DML3) glycosylases for 5mC and its oxidized derivatives. Relative to 5mC, DME and DML3 exhibited robust activity toward 5-hydroxymethylcytosine, limited activity for 5-carboxylcytosine, and no activity for 5-formylcytosine. We used homology modeling and mutational analysis of base excision and DNA binding to identify residues important for recognition of 5mC within the context of DNA and inside the enzyme active site. Our results indicate that the 5mC binding pocket is composed of residues from discrete domains and is responsible for discrimination against 5mC derivatives, and suggest that DME, ROS1, and DML3 utilize subtly different mechanisms to probe the DNA duplex for cytosine modifications.
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10 MeSH Terms
The nuclear pore complex function of Sec13 protein is required for cell survival during retinal development.
Niu X, Hong J, Zheng X, Melville DB, Knapik EW, Meng A, Peng J
(2014) J Biol Chem 289: 11971-85
MeSH Terms: Animals, Base Sequence, DNA Primers, In Situ Hybridization, Microscopy, Electron, Transmission, Nuclear Pore, RNA, Messenger, Real-Time Polymerase Chain Reaction, Retina, Zebrafish, Zebrafish Proteins
Show Abstract · Added April 26, 2017
Sec13 is a dual function protein, being a core component of both the COPII coat, which mediates protein trafficking from the endoplasmic reticulum to the Golgi apparatus, and the nuclear pore complex (NPC), which facilitates nucleo-cytoplasmic traffic. Here, we present a genetic model to differentiate the roles of these two functions of Sec13 in vivo. We report that sec13(sq198) mutant embryos develop small eyes that exhibit disrupted retinal lamination and that the mutant retina contains an excessive number of apoptotic cells. Surprisingly, we found that loss of COPII function by oligonucleotide-mediated gene knockdown of sec31a and sec31b or brefeldin A treatment did not disrupt retinal lamination, although it did result in digestive organ defects similar to those seen in sec13(sq198), suggesting that the digestive organ defects observed in sec13(sq198) are due to loss of COPII function, whereas the retinal lamination defects are due to loss of the NPC function. We showed that the retinal cells of sec13(sq198) failed to form proper nuclear pores, leading to a nuclear accumulation of total mRNA and abnormal activation of the p53-dependent apoptosis pathway, causing the retinal defect in sec13(sq198). Furthermore, we found that a mutant lacking Nup107, a key NPC-specific component, phenocopied the retinal lamination phenotype as observed in sec13(sq198). Our results demonstrate a requirement for the nuclear pore function of Sec13 in development of the retina and provide the first genetic evidence to differentiate the contributions of the NPC and the COPII functions of Sec13 during organogenesis.
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11 MeSH Terms
Quadruplex priming amplification for the detection of mRNA from surrogate patient samples.
Adams NM, Wang KK, Caprioli AC, Thomas LC, Kankia B, Haselton FR, Wright DW
(2014) Analyst 139: 1644-52
MeSH Terms: Base Sequence, Biosensing Techniques, Circular Dichroism, DNA Primers, Equipment Design, G-Quadruplexes, Humans, Magnets, Molecular Sequence Data, Nucleic Acid Amplification Techniques, RNA, Messenger, Spectrometry, Fluorescence, Xanthopterin
Show Abstract · Added May 27, 2014
Simple and rapid methods for detecting mRNA biomarkers from patient samples are valuable in settings with limited access to laboratory resources. In this report, we describe the development and evaluation of a self-contained assay to extract and quantify mRNA biomarkers from complex samples using a novel nucleic acid-based molecular sensor called quadruplex priming amplification (QPA). QPA is a simple and robust isothermal nucleic acid amplification method that exploits the stability of the G-quadruplex nucleotide structure to drive spontaneous strand melting from a specific DNA template sequence. Quantification of mRNA was enabled by integrating QPA with a magnetic bead-based extraction method using an mRNA-QPA interface reagent. The assay was found to maintain >90% of the maximum signal over a 4 °C range of operational temperatures (64-68 °C). QPA had a dynamic range spanning four orders of magnitude, with a limit of detection of ~20 pM template molecules using a highly controlled heating and optical system and a limit of detection of ~250 pM using a less optimal water bath and plate reader. These results demonstrate that this integrated approach has potential as a simple and effective mRNA biomarker extraction and detection assay for use in limited resource settings.
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13 MeSH Terms
Mycobacterium tuberculosis subverts the TLR-2-MyD88 pathway to facilitate its translocation into the cytosol.
Rahman A, Sobia P, Gupta N, Kaer LV, Das G
(2014) PLoS One 9: e86886
MeSH Terms: Animals, Bacterial Translocation, Cytosol, DNA Primers, Digitonin, Macrophages, Peritoneal, Mice, Mice, Inbred C57BL, Microscopy, Confocal, Mycobacterium tuberculosis, Myeloid Differentiation Factor 88, Real-Time Polymerase Chain Reaction, Signal Transduction, Thioglycolates, Toll-Like Receptor 2
Show Abstract · Added March 20, 2014
Mycobacterium tuberculosis (M.tb) has evolved mechanisms to evade its destruction in phagolysosomes, where it successfully survives and replicates within phagocytes. Recent studies have shown that virulent strains of M.tb can translocate from the phagosome into the cytosol of dendritic cells (DC). The molecular mechanisms by which virulent M.tb strains can escape the phagosome remain unknown. Here we show that the virulent M.tb strain H37Rv, but not the vaccine strain Bacille Calmette-Guérin (BCG), escapes from the phagolysosome and enters the cytosol by interfering with the TLR-2-MyD88 signaling pathway. Using H37Rv mutants, we further demonstrate that the region of difference-1 (RD-1) locus and ESAT-6, a gene within the RD-1 locus, play an important role in the capacity of M.tb to migrate from the phagosome to the cytosol of macrophages. H37Rv, BCG, H37RvΔRD1, and H37RvΔESAT6 were able to translocate to the cytosol in macrophages derived from TLR-2- and MyD88-deficient animals, whereas only virulent H37Rv was able to enter the cytosol in macrophages from wild type mice. Therefore, signaling through the TLR-2-MyD88 pathway in macrophages plays an important role in confining M.tb within phagolysomes. Virulent strains of M.tb have evolved mechanisms to subvert this pathway, thus facilitating their translocation to the cytosol and to escape the toxic microenvironment of the phagosome or phagolysosome.
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15 MeSH Terms
Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells.
Schultz MA, Hagan SS, Datta A, Zhang Y, Freeman ML, Sikka SC, Abdel-Mageed AB, Mondal D
(2014) PLoS One 9: e87204
MeSH Terms: Analysis of Variance, Cell Line, Tumor, Chromatin Immunoprecipitation, DNA Primers, Dihydrotestosterone, Electrophoretic Mobility Shift Assay, Humans, Immunoblotting, Luciferases, Male, NF-E2-Related Factor 2, Nuclear Respiratory Factor 1, Prostatic Neoplasms, Castration-Resistant, Real-Time Polymerase Chain Reaction, Receptors, Androgen, Transcriptional Activation
Show Abstract · Added March 13, 2014
Despite androgen deprivation therapy (ADT), persistent androgen receptor (AR) signaling enables outgrowth of castration resistant prostate cancer (CRPC). In prostate cancer (PCa) cells, ADT may enhance AR activity through induction of oxidative stress. Herein, we investigated the roles of Nrf1 and Nrf2, transcription factors that regulate antioxidant gene expression, on hormone-mediated AR transactivation using a syngeneic in vitro model of androgen dependent (LNCaP) and castration resistant (C4-2B) PCa cells. Dihydrotestosterone (DHT) stimulated transactivation of the androgen response element (ARE) was significantly greater in C4-2B cells than in LNCaP cells. DHT-induced AR transactivation was coupled with higher nuclear translocation of p65-Nrf1 in C4-2B cells, as compared to LNCaP cells. Conversely, DHT stimulation suppressed total Nrf2 levels in C4-2B cells but elevated total Nrf2 levels in LNCaP cells. Interestingly, siRNA mediated silencing of Nrf1 attenuated AR transactivation while p65-Nrf1 overexpression enhanced AR transactivation. Subsequent studies showed that Nrf1 physically interacts with AR and enhances AR's DNA-binding activity, suggesting that the p65-Nrf1 isoform is a potential AR coactivator. In contrast, Nrf2 suppressed AR-mediated transactivation by stimulating the nuclear accumulation of the p120-Nrf1 which suppressed AR transactivation. Quantitative RT-PCR studies further validated the inductive effects of p65-Nrf1 isoform on the androgen regulated genes, PSA and TMPRSS2. Therefore, our findings implicate differential roles of Nrf1 and Nrf2 in regulating AR transactivation in PCa cells. Our findings also indicate that the DHT-stimulated increase in p65-Nrf1 and the simultaneous suppression of both Nrf2 and p120-Nrf1 ultimately facilitates AR transactivation in CRPC cells.
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16 MeSH Terms
Adaptor protein2 (AP2) orchestrates CXCR2-mediated cell migration.
Raman D, Sai J, Hawkins O, Richmond A
(2014) Traffic 15: 451-69
MeSH Terms: Adaptor Protein Complex 2, Base Sequence, Chemotaxis, DNA Primers, Endocytosis, HEK293 Cells, HL-60 Cells, Humans, Mutagenesis, Site-Directed, Receptors, Interleukin-8B
Show Abstract · Added January 30, 2014
The chemokine receptor CXCR2 is vital for inflammation, wound healing, angiogenesis, cancer progression and metastasis. Adaptor protein 2 (AP2), a clathrin binding heterotetrameric protein comprised of α, β2, μ2 and σ2 subunits, facilitates clathrin-mediated endocytosis. Mutation of the LLKIL motif in the CXCR2 carboxyl-terminal domain (CTD) results in loss of AP2 binding to the receptor and loss of ligand-mediated receptor internalization and chemotaxis. AP2 knockdown also results in diminished ligand-mediated CXCR2 internalization, polarization and chemotaxis. Using knockdown/rescue approaches with AP2-μ2 mutants, the binding domains were characterized in reference to CXCR2 internalization and chemotaxis. When in an open conformation, μ2 Patch 1 and Patch 2 domains bind tightly to membrane PIP2 phospholipids. When AP2-μ2, is replaced with μ2 mutated in Patch 1 and/or Patch 2 domains, ligand-mediated receptor binding and internalization are not lost. However, chemotaxis requires AP2-μ2 Patch 1, but not Patch 2. AP2-σ2 has been demonstrated to bind dileucine motifs to facilitate internalization. Expression of AP2-σ2 V88D and V98S dominant negative mutants resulted in loss of CXCR2 mediated chemotaxis. Thus, AP2 binding to both membrane phosphatidylinositol phospholipids and dileucine motifs is crucial for directional migration or chemotaxis. Moreover, AP2-mediated receptor internalization can be dissociated from AP2-mediated chemotaxis.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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10 MeSH Terms
Insights into eukaryotic primer synthesis from structures of the p48 subunit of human DNA primase.
Vaithiyalingam S, Arnett DR, Aggarwal A, Eichman BF, Fanning E, Chazin WJ
(2014) J Mol Biol 426: 558-69
MeSH Terms: Binding Sites, Catalytic Domain, Crystallography, X-Ray, DNA Primase, DNA Primers, DNA Replication, DNA-Directed DNA Polymerase, Humans, Manganese, Protein Conformation, Protein Subunits, Saccharomyces cerevisiae
Show Abstract · Added March 7, 2014
DNA replication in all organisms requires polymerases to synthesize copies of the genome. DNA polymerases are unable to function on a bare template and require a primer. Primases are crucial RNA polymerases that perform the initial de novo synthesis, generating the first 8-10 nucleotides of the primer. Although structures of archaeal and bacterial primases have provided insights into general priming mechanisms, these proteins are not well conserved with heterodimeric (p48/p58) primases in eukaryotes. Here, we present X-ray crystal structures of the catalytic engine of a eukaryotic primase, which is contained in the p48 subunit. The structures of p48 reveal that eukaryotic primases maintain the conserved catalytic prim fold domain, but with a unique subdomain not found in the archaeal and bacterial primases. Calorimetry experiments reveal that Mn(2+) but not Mg(2+) significantly enhances the binding of nucleotide to primase, which correlates with higher catalytic efficiency in vitro. The structure of p48 with bound UTP and Mn(2+) provides insights into the mechanism of nucleotide synthesis by primase. Substitution of conserved residues involved in either metal or nucleotide binding alter nucleotide binding affinities, and yeast strains containing the corresponding Pri1p substitutions are not viable. Our results reveal that two residues (S160 and H166) in direct contact with the nucleotide were previously unrecognized as critical to the human primase active site. Comparing p48 structures to those of similar polymerases in different states of action suggests changes that would be required to attain a catalytically competent conformation capable of initiating dinucleotide synthesis.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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12 MeSH Terms