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  • 1
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    Insulin staining of ES cell progeny from insulin uptake (2003)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2003-01-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rajagopal, Jayaraj -- Anderson, William J -- Kume, Shoen -- Martinez, Olga I -- Melton, Douglas A -- New York, N.Y. -- Science. 2003 Jan 17;299(5605):363.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12532008" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies/immunology ; Apoptosis ; Cell Differentiation ; Cell Line ; Embryo, Mammalian/*cytology ; Humans ; Insulin/*analysis/genetics/immunology/*metabolism ; Islets of Langerhans/*cytology/metabolism ; Mice ; Microscopy, Confocal ; RNA, Messenger/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Stem Cells/*cytology/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy (1998)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1998-05-09
    Description: Hormones and neurotransmitters may mediate common responses through receptors that couple to the same class of heterotrimeric guanine nucleotide-binding (G) protein. For example, several receptors that couple to Gq class proteins can induce cardiomyocyte hypertrophy. Class-specific inhibition of Gq-mediated signaling was produced in the hearts of transgenic mice by targeted expression of a carboxyl-terminal peptide of the alpha subunit Galphaq. When pressure overload was surgically induced, the transgenic mice developed significantly less ventricular hypertrophy than control animals. The data demonstrate the role of myocardial Gq in the initiation of myocardial hypertrophy and indicate a possible strategy for preventing pathophysiological signaling by simultaneously blocking multiple receptors coupled to Gq.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Akhter, S A -- Luttrell, L M -- Rockman, H A -- Iaccarino, G -- Lefkowitz, R J -- Koch, W J -- HL-03041/HL/NHLBI NIH HHS/ -- HL-09436/HL/NHLBI NIH HHS/ -- HL-16037/HL/NHLBI NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1998 Apr 24;280(5363):574-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9554846" target="_blank"〉PubMed〈/a〉
    Keywords: Angiotensin II/pharmacology ; Animals ; Atrial Natriuretic Factor/genetics ; COS Cells ; Diglycerides/metabolism ; Enzyme Activation ; GTP-Binding Proteins/antagonists & inhibitors/genetics/*metabolism ; Gene Expression Regulation ; Gene Targeting ; Hypertrophy, Left Ventricular/*metabolism/prevention & control ; Inositol Phosphates/metabolism ; Mice ; Mice, Transgenic ; Mitogen-Activated Protein Kinase 1/metabolism ; Myocardium/*metabolism ; Peptide Fragments/genetics/metabolism ; Phenylephrine/pharmacology ; Receptors, Adrenergic, alpha/*metabolism ; Signal Transduction ; Transfection ; Transgenes ; Ventricular Pressure
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors (2001)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2001-01-06
    Description: Most traditional cytotoxic anticancer agents ablate the rapidly dividing epithelium of the hair follicle and induce alopecia (hair loss). Inhibition of cyclin-dependent kinase 2 (CDK2), a positive regulator of eukaryotic cell cycle progression, may represent a therapeutic strategy for prevention of chemotherapy-induced alopecia (CIA) by arresting the cell cycle and reducing the sensitivity of the epithelium to many cell cycle-active antitumor agents. Potent small-molecule inhibitors of CDK2 were developed using structure-based methods. Topical application of these compounds in a neonatal rat model of CIA reduced hair loss at the site of application in 33 to 50% of the animals. Thus, inhibition of CDK2 represents a potentially useful approach for the prevention of CIA in cancer patients.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davis, S T -- Benson, B G -- Bramson, H N -- Chapman, D E -- Dickerson, S H -- Dold, K M -- Eberwein, D J -- Edelstein, M -- Frye, S V -- Gampe Jr, R T -- Griffin, R J -- Harris, P A -- Hassell, A M -- Holmes, W D -- Hunter, R N -- Knick, V B -- Lackey, K -- Lovejoy, B -- Luzzio, M J -- Murray, D -- Parker, P -- Rocque, W J -- Shewchuk, L -- Veal, J M -- Walker, D H -- Kuyper, L F -- New York, N.Y. -- Science. 2001 Jan 5;291(5501):134-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Glaxo Wellcome Research and Development, Research Triangle Park, NC 27709, USA. std41085@glaxowellcome.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11141566" target="_blank"〉PubMed〈/a〉
    Keywords: Alopecia/*chemically induced/*prevention & control ; Animals ; Animals, Newborn ; Antineoplastic Agents/*toxicity ; Antineoplastic Combined Chemotherapy Protocols/toxicity ; Apoptosis/drug effects ; *CDC2-CDC28 Kinases ; Cell Cycle/drug effects ; Cell Line ; Cyclin-Dependent Kinase 2 ; Cyclin-Dependent Kinases/*antagonists & inhibitors/metabolism ; Cyclophosphamide/toxicity ; Cytoprotection/drug effects ; DNA/biosynthesis ; Doxorubicin/toxicity ; Drug Design ; Enzyme Inhibitors/chemical synthesis/chemistry/*pharmacology ; Epithelium/drug effects ; Etoposide/toxicity ; Hair Follicle/cytology/*drug effects ; Humans ; Indoles/chemical synthesis/chemistry/*pharmacology ; Mice ; Mice, SCID ; Phosphorylation ; Protein-Serine-Threonine Kinases/*antagonists & inhibitors/metabolism ; Rats ; Retinoblastoma Protein/metabolism ; Scalp/transplantation ; Sulfonamides/chemical synthesis/chemistry/*pharmacology ; Transplantation, Heterologous
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Impaired nociception and pain sensation in mice lacking the capsaicin receptor (2000)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2000-04-15
    Description: The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary sensory neurons of the "pain" pathway. Heterologously expressed VR1 can be activated by vanilloid compounds, protons, or heat (〉43 degrees C), but whether this channel contributes to chemical or thermal sensitivity in vivo is not known. Here, we demonstrate that sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli. VR1-/- mice showed normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked pain behavior, were impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation. Thus, VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Caterina, M J -- Leffler, A -- Malmberg, A B -- Martin, W J -- Trafton, J -- Petersen-Zeitz, K R -- Koltzenburg, M -- Basbaum, A I -- Julius, D -- NS07265/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2000 Apr 14;288(5464):306-13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143-0450, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10764638" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Body Temperature/drug effects ; Calcium/metabolism ; Capsaicin/metabolism/*pharmacology ; Cells, Cultured ; Diterpenes/pharmacology ; Ganglia, Spinal/cytology ; Gene Targeting ; Hot Temperature ; Hydrogen-Ion Concentration ; Inflammation/physiopathology ; Mice ; Mice, Knockout ; Nerve Fibers/physiology ; Neurons/physiology ; Neurons, Afferent/*physiology ; Nociceptors/*physiology ; Pain/*physiopathology ; Pain Threshold ; Receptors, Drug/*physiology ; Spinal Cord/cytology/physiology ; TRPV Cation Channels
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-07-13
    Description: Poly(ADP-ribose) polymerase-1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. PARP-1 is also a mediator of cell death after ischemia-reperfusion injury, glutamate excitotoxicity, and various inflammatory processes. We show that PARP-1 activation is required for translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and that AIF is necessary for PARP-1-dependent cell death. N-methyl-N'-nitro-N-nitrosoguanidine, H2O2, and N-methyl-d-aspartate induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP-1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP-1-dependent cytotoxicity. These data support a model in which PARP-1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, Seong-Woon -- Wang, Hongmin -- Poitras, Marc F -- Coombs, Carmen -- Bowers, William J -- Federoff, Howard J -- Poirier, Guy G -- Dawson, Ted M -- Dawson, Valina L -- New York, N.Y. -- Science. 2002 Jul 12;297(5579):259-63.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12114629" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Animals ; Antibodies/immunology ; *Apoptosis ; Apoptosis Inducing Factor ; Caspase Inhibitors ; Caspases/metabolism ; Cell Nucleus/metabolism ; Cells, Cultured ; Cytochrome c Group/metabolism ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Flavoproteins/immunology/*metabolism ; Hydrogen Peroxide/pharmacology ; Membrane Potentials ; Membrane Proteins/immunology/*metabolism ; Methylnitronitrosoguanidine/pharmacology ; Mice ; Mice, Knockout ; Mitochondria/metabolism/physiology ; N-Methylaspartate/metabolism/pharmacology ; NAD/metabolism ; Neurons/cytology/physiology ; Oxidative Stress ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/genetics/*metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
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    Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-12-14
    Description: The master circadian oscillator in the hypothalamic suprachiasmatic nucleus is entrained to the day/night cycle by retinal photoreceptors. Melanopsin (Opn4), an opsin-based photopigment, is a primary candidate for photoreceptor-mediated entrainment. To investigate the functional role of melanopsin in light resetting of the oscillator, we generated melanopsin-null mice (Opn4-/-). These mice entrain to a light/dark cycle and do not exhibit any overt defect in circadian activity rhythms under constant darkness. However, they display severely attenuated phase resetting in response to brief pulses of monochromatic light, highlighting the critical role of melanopsin in circadian photoentrainment in mammals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Panda, Satchidananda -- Sato, Trey K -- Castrucci, Ana Maria -- Rollag, Mark D -- DeGrip, Willem J -- Hogenesch, John B -- Provencio, Ignacio -- Kay, Steve A -- MH 62405/MH/NIMH NIH HHS/ -- MH51573/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2002 Dec 13;298(5601):2213-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, CA 92121, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12481141" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Clocks/physiology ; Circadian Rhythm/*physiology ; Darkness ; Female ; Gene Targeting ; *Light ; Light Signal Transduction ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Motor Activity ; Retinal Ganglion Cells/physiology ; Rod Opsins/genetics/*physiology ; Suprachiasmatic Nucleus/physiology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
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    Down-regulation of the macrophage lineage through interaction with OX2 (CD200) (2000)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2000-12-02
    Description: OX2 (CD200) is a broadly expressed membrane glycoprotein, shown here to be important for regulation of the macrophage lineage. In mice lacking CD200, macrophage lineage cells, including brain microglia, exhibited an activated phenotype and were more numerous. Upon facial nerve transection, damaged CD200-deficient neurons elicited an accelerated microglial response. Lack of CD200 resulted in a more rapid onset of experimental autoimmune encephalomyelitis (EAE). Outside the brain, disruption of CD200-CD200 receptor interaction precipitated susceptibility to collagen-induced arthritis (CIA) in mice normally resistant to this disease. Thus, in diverse tissues OX2 delivers an inhibitory signal for the macrophage lineage.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hoek, R M -- Ruuls, S R -- Murphy, C A -- Wright, G J -- Goddard, R -- Zurawski, S M -- Blom, B -- Homola, M E -- Streit, W J -- Brown, M H -- Barclay, A N -- Sedgwick, J D -- New York, N.Y. -- Science. 2000 Dec 1;290(5497):1768-71.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉DNAX Research Institute of Molecular and Cellular Biology, 901 California Avenue, Palo Alto, CA 94304, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11099416" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD ; Antigens, Surface/*metabolism ; Arthritis, Experimental/immunology/pathology ; Cell Lineage ; Central Nervous System/immunology/pathology ; Denervation ; *Down-Regulation ; Encephalomyelitis, Autoimmune, Experimental/immunology/pathology ; Facial Nerve ; Gene Targeting ; Joints/immunology/pathology ; Lymph Nodes/cytology ; Macrophage Activation ; Macrophages/cytology/metabolism/*physiology ; Mice ; Mice, Inbred C57BL ; Microglia/physiology ; Neurons/physiology ; Rats ; Receptors, Immunologic/metabolism ; Spleen/cytology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
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    A critical role for IL-21 in regulating immunoglobulin production (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-11-26
    Description: The cytokine interleukin-21 (IL-21) is closely related to IL-2 and IL-15, and their receptors all share the common cytokine receptor gamma chain, gammac, which is mutated in humans with X-linked severe combined immunodeficiency disease (XSCID). We demonstrate that, although mice deficient in the receptor for IL-21 (IL-21R) have normal lymphoid development, after immunization, these animals have higher production of the immunoglobulin IgE, but lower IgG1, than wild-type animals. Mice lacking both IL-4 and IL-21R exhibited a significantly more pronounced phenotype, with dysgammaglobulinemia, characterized primarily by a severely impaired IgG response. Thus, IL-21 has a significant influence on the regulation of B cell function in vivo and cooperates with IL-4. This suggests that these gammac-dependent cytokines may be those whose inactivation is primarily responsible for the B cell defect in humans with XSCID.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ozaki, Katsutoshi -- Spolski, Rosanne -- Feng, Carl G -- Qi, Chen-Feng -- Cheng, Jun -- Sher, Alan -- Morse, Herbert C 3rd -- Liu, Chengyu -- Schwartzberg, Pamela L -- Leonard, Warren J -- New York, N.Y. -- Science. 2002 Nov 22;298(5598):1630-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12446913" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibody-Producing Cells/immunology ; B-Lymphocytes/*immunology ; CD4-Positive T-Lymphocytes/immunology ; Cells, Cultured ; Gene Targeting ; Genetic Diseases, X-Linked/immunology ; Humans ; Immunization ; Immunoglobulin E/*biosynthesis ; Immunoglobulin G/*biosynthesis ; Immunoglobulins/biosynthesis ; Immunologic Memory ; Interferon-gamma/biosynthesis ; Interleukin-21 Receptor alpha Subunit ; Interleukin-4/biosynthesis/physiology ; Interleukins/*physiology ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Receptors, Interleukin/genetics/metabolism ; Receptors, Interleukin-21 ; Severe Combined Immunodeficiency/immunology ; Signal Transduction ; T-Lymphocytes/immunology ; Toxoplasmosis, Animal/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
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    Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine (1997)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1997-06-13
    Description: Two families of small peptides that bind to the human thrombopoietin receptor and compete with the binding of the natural ligand thrombopoietin (TPO) were identified from recombinant peptide libraries. The sequences of these peptides were not found in the primary sequence of TPO. Screening libraries of variants of one of these families under affinity-selective conditions yielded a 14-amino acid peptide (Ile-Glu-Gly-Pro-Thr-Leu-Arg-Gln-Trp-Leu-Ala-Ala-Arg-Ala) with high affinity (dissociation constant approximately 2 nanomolar) that stimulates the proliferation of a TPO-responsive Ba/F3 cell line with a median effective concentration (EC50) of 400 nanomolar. Dimerization of this peptide by a carboxyl-terminal linkage to a lysine branch produced a compound with an EC50 of 100 picomolar, which was equipotent to the 332-amino acid natural cytokine in cell-based assays. The peptide dimer also stimulated the in vitro proliferation and maturation of megakaryocytes from human bone marrow cells and promoted an increase in platelet count when administered to normal mice.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cwirla, S E -- Balasubramanian, P -- Duffin, D J -- Wagstrom, C R -- Gates, C M -- Singer, S C -- Davis, A M -- Tansik, R L -- Mattheakis, L C -- Boytos, C M -- Schatz, P J -- Baccanari, D P -- Wrighton, N C -- Barrett, R W -- Dower, W J -- New York, N.Y. -- Science. 1997 Jun 13;276(5319):1696-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Affymax Research Institute, 4001 Miranda Avenue, Palo Alto, CA 94304, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9180079" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding, Competitive ; Blood Platelets/cytology ; Cell Division ; Cell Line ; Cells, Cultured ; Consensus Sequence ; Dimerization ; Erythropoietin/pharmacology ; Hematopoiesis/drug effects ; Humans ; Megakaryocytes/cytology ; Mice ; Molecular Sequence Data ; *Neoplasm Proteins ; Oligopeptides/*metabolism/*pharmacology ; Peptide Library ; Peptides/metabolism/pharmacology ; Platelet Count ; Proto-Oncogene Proteins/*agonists/metabolism ; *Receptors, Cytokine ; Receptors, Thrombopoietin ; Recombinant Proteins/metabolism/pharmacology ; Thrombopoietin/*metabolism/pharmacology ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
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    Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-09-03
    Description: Accumulation of neurotoxic amyloid-beta is a major hallmark of Alzheimer's disease. Formation of amyloid-beta is catalysed by gamma-secretase, a protease with numerous substrates. Little is known about the molecular mechanisms that confer substrate specificity on this potentially promiscuous enzyme. Knowledge of the mechanisms underlying its selectivity is critical for the development of clinically effective gamma-secretase inhibitors that can reduce amyloid-beta formation without impairing cleavage of other gamma-secretase substrates, especially Notch, which is essential for normal biological functions. Here we report the discovery of a novel gamma-secretase activating protein (GSAP) that drastically and selectively increases amyloid-beta production through a mechanism involving its interactions with both gamma-secretase and its substrate, the amyloid precursor protein carboxy-terminal fragment (APP-CTF). GSAP does not interact with Notch, nor does it affect its cleavage. Recombinant GSAP stimulates amyloid-beta production in vitro. Reducing GSAP concentrations in cell lines decreases amyloid-beta concentrations. Knockdown of GSAP in a mouse model of Alzheimer's disease reduces levels of amyloid-beta and plaque development. GSAP represents a type of gamma-secretase regulator that directs enzyme specificity by interacting with a specific substrate. We demonstrate that imatinib, an anticancer drug previously found to inhibit amyloid-beta formation without affecting Notch cleavage, achieves its amyloid-beta-lowering effect by preventing GSAP interaction with the gamma-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-beta-lowering therapeutic target without affecting other key functions of gamma-secretase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936959/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Gen -- Luo, Wenjie -- Li, Peng -- Remmers, Christine -- Netzer, William J -- Hendrick, Joseph -- Bettayeb, Karima -- Flajolet, Marc -- Gorelick, Fred -- Wennogle, Lawrence P -- Greengard, Paul -- AG09464/AG/NIA NIH HHS/ -- P01 AG009464/AG/NIA NIH HHS/ -- P01 AG009464-16A10010/AG/NIA NIH HHS/ -- T32 DK007017/DK/NIDDK NIH HHS/ -- England -- Nature. 2010 Sep 2;467(7311):95-8. doi: 10.1038/nature09325.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20811458" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/*metabolism ; Amyloid Precursor Protein Secretases/chemistry/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/chemistry/metabolism ; Animals ; Benzamides ; Cell Line ; Disease Models, Animal ; Gene Knockdown Techniques ; Humans ; Imatinib Mesylate ; Mice ; Peptide Fragments/metabolism ; Piperazines/pharmacology ; Proteins/*antagonists & inhibitors/genetics/*metabolism ; Pyrimidines/pharmacology ; RNA Interference ; Receptor, Notch1/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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