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Results: 161 to 167 of 167

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Disruption of IRS-2 causes type 2 diabetes in mice.
Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner-Weir S, White MF
(1998) Nature 391: 900-4
MeSH Terms: Animals, Blood Glucose, Cloning, Molecular, Diabetes Mellitus, Type 2, Female, Gene Targeting, Humans, Insulin, Insulin Receptor Substrate Proteins, Insulin Resistance, Intracellular Signaling Peptides and Proteins, Islets of Langerhans, Liver, Male, Mice, Mice, Inbred C57BL, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Receptor, Insulin, Recombination, Genetic, Signal Transduction
Show Abstract · Added April 24, 2015
Human type 2 diabetes is characterized by defects in both insulin action and insulin secretion. It has been difficult to identify a single molecular abnormality underlying these features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytokines. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin. Here we show that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic beta-cell function. IRS-2-deficient mice show progressive deterioration of glucose homeostasis because of insulin resistance in the liver and skeletal muscle and a lack of beta-cell compensation for this insulin resistance. Our results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes.
1 Communities
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23 MeSH Terms
Feedback regulation is central to Delta-Notch signalling required for Drosophila wing vein morphogenesis.
Huppert SS, Jacobsen TL, Muskavitch MA
(1997) Development 124: 3283-91
MeSH Terms: Animals, Animals, Genetically Modified, Drosophila, Drosophila Proteins, Feedback, Gene Expression Regulation, Developmental, Genes, Insect, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Metamorphosis, Biological, Phenotype, Pupa, Receptors, Notch, Signal Transduction, Wings, Animal
Show Abstract · Added January 11, 2011
Delta and Notch are required for partitioning of vein and intervein cell fates within the provein during Drosophila metamorphosis. We find that partitioning of these fates is dependent on Delta-mediated signalling from 22 to 30 hours after puparium formation at 25 degrees C. Within the provein, Delta is expressed more highly in central provein cells (presumptive vein cells) and Notch is expressed more highly in lateral provein cells (presumptive intervein cells). Accumulation of Notch in presumptive intervein cells is dependent on Delta signalling activity in presumptive vein cells and constitutive Notch receptor activity represses Delta accumulation in presumptive vein cells. When Delta protein expression is elevated ectopically in presumptive intervein cells, complementary Delta and Notch expression patterns in provein cells are reversed, and vein loss occurs because central provein cells are unable to stably adopt the vein cell fate. Our findings imply that Delta-Notch signalling exerts feedback regulation on Delta and Notch expression during metamorphic wing vein development, and that the resultant asymmetries in Delta and Notch expression underlie the proper specification of vein and intervein cell fates within the provein.
1 Communities
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15 MeSH Terms
The dynamics of neurogenic signalling underlying bristle development in Drosophila melanogaster.
Parks AL, Huppert SS, Muskavitch MA
(1997) Mech Dev 63: 61-74
MeSH Terms: Animals, Animals, Genetically Modified, Basic Helix-Loop-Helix Transcription Factors, DNA Transposable Elements, DNA-Binding Proteins, Drosophila Proteins, Drosophila melanogaster, Gene Expression Regulation, Developmental, Genes, Insect, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Nervous System Physiological Phenomena, Pupa, Sensory Receptor Cells, Signal Transduction, Transcription Factors, Vibrissae
Show Abstract · Added January 11, 2011
We have examined expression of the neurogenic gene, Delta (Dl), and the regulatory relationships between the Delta-Notch signalling pathway and the proneural gene, achaete, during microchaeta development in Drosophila. Delta is expressed in all microchaeta proneural cells and microchaeta sensory organ precursors (SOPs) and is expressed dynamically in SOP progeny. We find that Delta expression in microchaeta proneural cells is detected prior to the onset of achaete expression and arises normally in the absence of achaete/scute function, indicating that initial Delta expression in the notum is not dependent on proneural gene function. Activation of the Delta-Notch pathway results in loss of Delta protein accumulation, suggesting that Delta expression is regulated, in part, by Delta-Notch signalling activity. We find that Delta signalling is required for correct delineation of early proneural gene expression in developing nota. Within microchaeta proneural stripes, we demonstrate that Delta-Notch signalling prohibits adoption of the SOP fate by repressing expression of proneural genes.
1 Communities
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17 MeSH Terms
DNA-dependent protein kinase is not required for accumulation of p53 or cell cycle arrest after DNA damage.
Rathmell WK, Kaufmann WK, Hurt JC, Byrd LL, Chu G
(1997) Cancer Res 57: 68-74
MeSH Terms: Animals, Animals, Newborn, CCAAT-Enhancer-Binding Proteins, Cricetinae, Cyclin-Dependent Kinase Inhibitor p21, Cyclins, DNA, DNA Damage, DNA-Activated Protein Kinase, DNA-Binding Proteins, Fibroblasts, G1 Phase, G2 Phase, Intracellular Signaling Peptides and Proteins, Mice, Mice, Inbred BALB C, Mice, SCID, Protein-Serine-Threonine Kinases, Proteins, Transcription Factor CHOP, Transcription Factors, Transcription, Genetic, Tumor Suppressor Protein p53
Show Abstract · Added October 17, 2015
In response to DNA damage, cells transduce a signal that leads to accumulation and activation of p53 protein, transcriptional induction of several genes, including p21, gadd45, and gadd153, and cell cycle arrest. One hypothesis is that the signal is mediated by DNA-dependent protein kinase (DNA-PK), which consists of a catalytic subunit (DNA-PKcs) and a regulatory subunit (Ku). DNA-PK has several characteristics that support this hypothesis: Ku binds to DNA damaged by nicks or double-strand breaks, DNA-PKcs is activated when Ku binds to DNA, DNA-PK will phosphorylate p53 and other cell cycle regulatory proteins in vitro, and DNA-PKcs shares homology with ATM, which is mutated in ataxia telangiectasia and involved in signaling the p53 response to ionizing radiation. The hypothesis was tested by analyzing early passage fibroblasts from severe combined immunodeficient mice, which are deficient in DNA-PK. After exposure to ionizing radiation, UV radiation, or methyl methane-sulfonate, severe combined immunodeficient and wild-type cells were indistinguishable in their response. The accumulation of p53, induction of p21, gadd45, and gadd153, and arrest of the cell cycle in G1 and G2 occurred normally. Therefore, DNA-PK is not required for the p53 response or cell cycle arrest after DNA damage.
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23 MeSH Terms
Disruption of epithelial gamma delta T cell repertoires by mutation of the Syk tyrosine kinase.
Mallick-Wood CA, Pao W, Cheng AM, Lewis JM, Kulkarni S, Bolen JB, Rowley B, Tigelaar RE, Pawson T, Hayday AC
(1996) Proc Natl Acad Sci U S A 93: 9704-9
MeSH Terms: Animals, Electrophoresis, Polyacrylamide Gel, Enzyme Precursors, Epithelial Cells, Epithelium, Flow Cytometry, Intracellular Signaling Peptides and Proteins, Lymphocytes, Mice, Mutagenesis, Site-Directed, Polymerase Chain Reaction, Polymorphism, Restriction Fragment Length, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, gamma-delta, Syk Kinase
Show Abstract · Added March 24, 2014
Chimeric mice in which lymphocytes are deficient in the Syk tyrosine kinase have been created. Compared with Syk-positive controls, mice with Syk -/- lymphocytes display substantial depletion of intraepithelial gamma delta T cells in the skin and gut, with developmental arrest occurring after antigen receptor gene rearrangement. In this dependence on Syk, subsets of intraepithelial gamma delta T cells are similar to B cells, but distinct from splenic gamma delta T cells that develop and expand in Syk-deficient mice. The characteristic associations of certain T-cell receptor V gamma/V delta gene rearrangements with specific epithelia are also disrupted by Syk deficiency.
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15 MeSH Terms
Syk tyrosine kinase required for mouse viability and B-cell development.
Cheng AM, Rowley B, Pao W, Hayday A, Bolen JB, Pawson T
(1995) Nature 378: 303-6
MeSH Terms: Animals, B-Lymphocytes, Base Sequence, Bone Marrow Cells, Cell Differentiation, Clone Cells, DNA Primers, Enzyme Precursors, Exons, Fetal Death, Fetal Viability, Hematopoietic Stem Cell Transplantation, Hemorrhage, Humans, Intracellular Signaling Peptides and Proteins, Liver, Mice, Molecular Sequence Data, Mutagenesis, Polymerase Chain Reaction, Polymorphism, Restriction Fragment Length, Protein-Tyrosine Kinases, Receptors, Antigen, B-Cell, Signal Transduction, Syk Kinase
Show Abstract · Added March 24, 2014
The Syk cytoplasmic protein-tyrosine kinase has two amino-terminal SH2 domains and a carboxy-terminal catalytic domain. Syk, and its close relative ZAP-70, are apparently pivotal in coupling antigen- and Fc-receptors to downstream signalling events. Syk associates with activated Fc receptors, the T cell receptor complex and the B-cell antigen-receptor complex (BCR) in immature and mature B lymphocytes. On receptor activation, the tandem SH2 domains of Syk bind dual phosphotyrosine sites in the conserved ITAM motifs of receptor signalling chains, such as the immunoglobulin alpha and beta-chains of the BCR, leading to Syk activation. Here we have investigated Syk function in vivo by generating a mouse strain with a targeted mutation in the syk gene. Homozygous syk mutants suffered severe haemorrhaging as embryos and died perinatally, indicating that Syk has a critical role in maintaining vascular integrity or in wound healing during embryogenesis. Analysis of syk-/- lymphoid cells showed that the syk mutation impaired the differentiation of B-lineage cells, apparently by disrupting signalling from the pre-BCR complex and thereby preventing the clonal expansion, and further maturation, of pre-B cells.
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25 MeSH Terms
Identification of a protein kinase activity in rabbit reticulocytes that phosphorylates the mRNA cap binding protein.
McMullin EL, Haas DW, Abramson RD, Thach RE, Merrick WC, Hagedorn CH
(1988) Biochem Biophys Res Commun 153: 340-6
MeSH Terms: Animals, Carrier Proteins, Eukaryotic Initiation Factor-4E, Eukaryotic Initiation Factor-4F, Intracellular Signaling Peptides and Proteins, Peptide Initiation Factors, Phosphorylation, Protein Kinases, Protein-Serine-Threonine Kinases, RNA Cap-Binding Proteins, RNA Caps, Rabbits, Reticulocytes
Show Abstract · Added March 13, 2015
The 25 kDa mRNA cap binding protein can be purified in a partially phosphorylated state and the extent of its phosphorylation appears to be regulated during heat shock and mitosis in mammalian cells. We demonstrated that a nonabundant serine protein kinase activity exists in rabbit reticulocytes that phosphorylates the 25 kDa cap binding protein in both the free (eIF-4E) and complexed (eIF-4F) state. This kinase was not inhibited by the cAMP-dependent protein kinase inhibitory peptide IAAGRTGRRNAIHDILVAA, did not phosphorylate S6 ribosomal protein, did not phosphorylate p220 of eIF-4F as protein kinase C does and no other substrates for this kinase were apparent in reticulocyte ribosomal salt wash. The molecular identity of this kinase, the specific site(s) of eIF-4E that it phosphorylates and its in vivo regulatory role remain to be studied.
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13 MeSH Terms