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  • 1
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    Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-04-10
    Description: Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide (As2O3) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells, PML-RARalpha (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RARalpha degradation is triggered by their SUMOylation, but the mechanism by which As2O3 induces this posttranslational modification is unclear. Here we show that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RARalpha and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation. The identification of PML as a direct target of As2O3 provides new insights into the drug's mechanism of action and its specificity for APL.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Xiao-Wei -- Yan, Xiao-Jing -- Zhou, Zi-Ren -- Yang, Fei-Fei -- Wu, Zi-Yu -- Sun, Hong-Bin -- Liang, Wen-Xue -- Song, Ai-Xin -- Lallemand-Breitenbach, Valerie -- Jeanne, Marion -- Zhang, Qun-Ye -- Yang, Huai-Yu -- Huang, Qiu-Hua -- Zhou, Guang-Biao -- Tong, Jian-Hua -- Zhang, Yan -- Wu, Ji-Hui -- Hu, Hong-Yu -- de The, Hugues -- Chen, Sai-Juan -- Chen, Zhu -- New York, N.Y. -- Science. 2010 Apr 9;328(5975):240-3. doi: 10.1126/science.1183424.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20378816" target="_blank"〉PubMed〈/a〉
    Keywords: Arsenic/*metabolism ; Arsenicals/*metabolism/*pharmacology ; Cell Line ; Humans ; Leukemia, Promyelocytic, Acute/drug therapy/genetics ; Mutant Proteins/chemistry/metabolism ; Mutation ; Nuclear Proteins/chemistry/genetics/*metabolism ; Oncogene Proteins, Fusion/chemistry/genetics/*metabolism ; Oxazines/metabolism ; Oxides/*metabolism/*pharmacology ; Protein Conformation ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, Retinoic Acid/metabolism ; Recombinant Fusion Proteins/chemistry/metabolism ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Transcription Factors/chemistry/genetics/*metabolism ; Tumor Suppressor Proteins/chemistry/genetics/*metabolism ; Ubiquitination ; Zinc Fingers
    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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  • 2
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    Inhibition of excess nodal signaling during mouse gastrulation by the transcriptional corepressor DRAP1 (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-12-10
    Description: The formation and patterning of mesoderm during mammalian gastrulation require the activity of Nodal, a secreted mesoderm-inducing factor of the transforming growth factor-beta (TGF-beta) family. Here we show that the transcriptional corepressor DRAP1 has a very specific role in regulation of Nodal activity during mouse embryogenesis. We find that loss of Drap1 leads to severe gastrulation defects that are consistent with increased expression of Nodal and can be partially suppressed by Nodal heterozygosity. Biochemical studies indicate that DRAP1 interacts with and inhibits DNA binding by the winged-helix transcription factor FoxH1 (FAST), a critical component of a positive feedback loop for Nodal activity. We propose that DRAP1 limits the spread of a morphogenetic signal by down-modulating the response to the Nodal autoregulatory loop.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Iratni, Rabah -- Yan, Yu-Ting -- Chen, Canhe -- Ding, Jixiang -- Zhang, Yi -- Price, Sandy M -- Reinberg, Danny -- Shen, Michael M -- New York, N.Y. -- Science. 2002 Dec 6;298(5600):1996-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Biochemistry, Division of Nucleic Acids Enzymology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12471260" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Cell Line ; Crosses, Genetic ; DNA/metabolism ; DNA-Binding Proteins/metabolism ; *Embryonic and Fetal Development ; Female ; Forkhead Transcription Factors ; Gastrula/*physiology ; Gene Expression Regulation, Developmental ; Gene Targeting ; Heterozygote ; In Situ Hybridization ; Left-Right Determination Factors ; Male ; Mesoderm/cytology/physiology ; Mice ; Morphogenesis ; Mutation ; Nodal Protein ; Phenotype ; Protein Binding ; RNA Interference ; Recombinant Fusion Proteins/metabolism ; Repressor Proteins/genetics/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; *Signal Transduction ; Transcription Factors/metabolism ; Transforming Growth Factor beta/genetics/*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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  • 3
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    Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-07-27
    Description: Glycoprotein adhesion receptors such as selectins contribute to tissue injury in stroke. Ischemic neurons strongly expressed C1q, which may target them for complement-mediated attack or C1qRp-mediated clearance. A hybrid molecule was used to simultaneously inhibit both complement activation and selectin-mediated adhesion. The extracellular domain of soluble complement receptor-1 (sCR1) was sialyl Lewis x glycosylated (sCR1sLex) to inhibit complement activation and endothelial-platelet-leukocyte interactions. sCR1 and sCR1sLex colocalized to ischemic cerebral microvessels and C1q-expressing neurons, inhibited neutrophil and platelet accumulation, and reduced cerebral infarct volumes. Additional benefit was conferred by sialyl Lewis x glycosylation of the unmodified parent sCR1 molecule.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, J -- Kim, L J -- Mealey, R -- Marsh, H C Jr -- Zhang, Y -- Tenner, A J -- Connolly, E S Jr -- Pinsky, D J -- R01 HL55397/HL/NHLBI NIH HHS/ -- R01 HL59488/HL/NHLBI NIH HHS/ -- R01 NS35144/NS/NINDS NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1999 Jul 23;285(5427):595-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10417391" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Platelets/physiology ; Cell Adhesion ; Cerebral Cortex/blood supply/immunology/metabolism ; Cerebral Infarction/drug therapy ; Cerebrovascular Circulation ; Cerebrovascular Disorders/*drug therapy/immunology/physiopathology ; Complement Activation ; Complement C1q/metabolism ; Glycosylation ; Humans ; Ischemic Attack, Transient/*drug therapy/immunology/physiopathology ; Leukocytes/physiology ; Mice ; Neurons/immunology/metabolism ; Neuroprotective Agents/administration & dosage/adverse ; effects/metabolism/*therapeutic use ; Neutrophils/physiology ; Oligosaccharides/administration & dosage/adverse effects/metabolism/*therapeutic ; use ; Platelet Adhesiveness ; Receptors, Complement/administration & dosage/metabolism/*therapeutic use ; Reperfusion Injury/drug therapy/immunology/metabolism ; Selectins/metabolism ; Time Factors
    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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    A p53 amino-terminal nuclear export signal inhibited by DNA damage-induced phosphorylation (2001)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2001-06-09
    Description: The p53 protein is present in low amounts in normally growing cells and is activated in response to physiological insults. MDM2 regulates p53 either through inhibiting p53's transactivating function in the nucleus or by targeting p53 degradation in the cytoplasm. We identified a previously unknown nuclear export signal (NES) in the amino terminus of p53, spanning residues 11 to 27 and containing two serine residues phosphorylated after DNA damage, which was required for p53 nuclear export in colloboration with the carboxyl-terminal NES. Serine-15-phosphorylated p53 induced by ultraviolet irradiation was not exported. Thus, DNA damage-induced phosphorylation may achieve optimal p53 activation by inhibiting both MDM2 binding to, and the nuclear export of, p53.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Y -- Xiong, Y -- CA65572/CA/NCI NIH HHS/ -- K01 CA087580/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2001 Jun 8;292(5523):1910-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, and Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, NC 27599-7295, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11397945" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Amino Acid Sequence ; Animals ; Cell Fusion ; Cell Line ; Cell Nucleus/*metabolism ; Cells, Cultured ; Cytoplasm/metabolism ; *DNA Damage ; Mice ; Molecular Sequence Data ; Mutation ; *Nuclear Proteins ; Phosphorylation ; Phosphoserine/metabolism ; *Protein Sorting Signals ; Protein Structure, Tertiary ; Proteins/genetics/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-mdm2 ; Recombinant Fusion Proteins/metabolism ; Transfection ; Tumor Suppressor Protein p14ARF ; Tumor Suppressor Protein p53/*chemistry/genetics/*metabolism ; Ubiquitins/metabolism ; Ultraviolet Rays
    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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    Discovery of a small molecule insulin mimetic with antidiabetic activity in mice (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-05-13
    Description: Insulin elicits a spectrum of biological responses by binding to its cell surface receptor. In a screen for small molecules that activate the human insulin receptor tyrosine kinase, a nonpeptidyl fungal metabolite (L-783,281) was identified that acted as an insulin mimetic in several biochemical and cellular assays. The compound was selective for insulin receptor versus insulin-like growth factor I (IGFI) receptor and other receptor tyrosine kinases. Oral administration of L-783,281 to two mouse models of diabetes resulted in significant lowering in blood glucose levels. These results demonstrate the feasibility of discovering novel insulin receptor activators that may lead to new therapies for diabetes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, B -- Salituro, G -- Szalkowski, D -- Li, Z -- Zhang, Y -- Royo, I -- Vilella, D -- Diez, M T -- Pelaez, F -- Ruby, C -- Kendall, R L -- Mao, X -- Griffin, P -- Calaycay, J -- Zierath, J R -- Heck, J V -- Smith, R G -- Moller, D E -- New York, N.Y. -- Science. 1999 May 7;284(5416):974-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Endocrinology, Merck Research Laboratories, R80W250, Post Office Box 2000, Rahway, NJ 07065, USA. bei_zhang@merck.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10320380" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Ascomycota/*metabolism ; Binding Sites ; Blood Glucose/metabolism ; CHO Cells ; Cricetinae ; Diabetes Mellitus, Type 2/*drug therapy ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Enzyme Activation ; Glucose Tolerance Test ; Hyperglycemia/drug therapy ; Hypoglycemic Agents/chemistry/metabolism/*pharmacology/therapeutic use ; Indoles/chemistry/metabolism/*pharmacology/therapeutic use ; Insulin/blood/metabolism/*pharmacology ; Insulin Receptor Substrate Proteins ; Mice ; Mice, Mutant Strains ; Mice, Obese ; Molecular Mimicry ; Phosphoproteins/metabolism ; Phosphorylation ; Protein Conformation/drug effects ; Receptor, Epidermal Growth Factor/metabolism ; Receptor, IGF Type 1/metabolism ; Receptor, Insulin/chemistry/*metabolism ; Signal Transduction
    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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    betaAR signaling required for diet-induced thermogenesis and obesity resistance (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-08-06
    Description: Excessive caloric intake is thought to be sensed by the brain, which then activates thermogenesis as a means of preventing obesity. The sympathetic nervous system, through beta-adrenergic receptor (betaAR) action on target tissues, is likely the efferent arm of this homeostatic mechanism. To test this hypothesis, we created mice that lack the three known betaARs (beta-less mice). beta-less mice on a Chow diet had a reduced metabolic rate and were slightly obese. On a high-fat diet, beta-less mice, in contrast to wild-type mice, developed massive obesity that was due entirely to a failure of diet-induced thermogenesis. These findings establish that betaARs are necessary for diet-induced thermogenesis and that this efferent pathway plays a critical role in the body's defense against diet-induced obesity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bachman, Eric S -- Dhillon, Harveen -- Zhang, Chen-Yu -- Cinti, Saverio -- Bianco, Antonio C -- Kobilka, Brian K -- Lowell, Bradford B -- New York, N.Y. -- Science. 2002 Aug 2;297(5582):843-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, MA 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12161655" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/drug effects/metabolism ; Animals ; Basal Metabolism/drug effects ; Body Temperature/drug effects ; Body Weight/drug effects/genetics ; *Diet ; Dietary Fats/administration & dosage/pharmacology ; Energy Intake ; Female ; Homeostasis/drug effects ; Immunohistochemistry ; Male ; Mice ; Mice, Knockout ; Obesity/blood/genetics/*metabolism/prevention & control ; Oxygen Consumption/drug effects ; Phenotype ; Receptors, Adrenergic, beta/genetics/*metabolism ; *Signal Transduction/drug effects ; Sympathetic Nervous System/drug effects/physiology ; Thermogenesis/genetics/*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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    Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-07-20
    Description: DNA methylation is one of the best-characterized epigenetic modifications. Although the enzymes that catalyse DNA methylation have been characterized, enzymes responsible for demethylation have been elusive. A recent study indicates that the human TET1 protein could catalyse the conversion of 5-methylcytosine (5mC) of DNA to 5-hydroxymethylcytosine (5hmC), raising the possibility that DNA demethylation may be a Tet1-mediated process. Here we extend this study by demonstrating that all three mouse Tet proteins (Tet1, Tet2 and Tet3) can also catalyse a similar reaction. Tet1 has an important role in mouse embryonic stem (ES) cell maintenance through maintaining the expression of Nanog in ES cells. Downregulation of Nanog via Tet1 knockdown correlates with methylation of the Nanog promoter, supporting a role for Tet1 in regulating DNA methylation status. Furthermore, knockdown of Tet1 in pre-implantation embryos results in a bias towards trophectoderm differentiation. Thus, our studies not only uncover the enzymatic activity of the Tet proteins, but also demonstrate a role for Tet1 in ES cell maintenance and inner cell mass cell specification.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491567/" 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/PMC3491567/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ito, Shinsuke -- D'Alessio, Ana C -- Taranova, Olena V -- Hong, Kwonho -- Sowers, Lawrence C -- Zhang, Yi -- CA084487/CA/NCI NIH HHS/ -- GM68804/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Aug 26;466(7310):1129-33. doi: 10.1038/nature09303.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20639862" target="_blank"〉PubMed〈/a〉
    Keywords: 5-Methylcytosine/*metabolism ; Alkaline Phosphatase/metabolism ; Animals ; Blastocyst Inner Cell Mass/*metabolism ; Cell Proliferation ; Cytosine/*analogs & derivatives/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Embryonic Stem Cells/*cytology ; Gene Expression Regulation, Developmental ; Gene Knockdown Techniques ; Homeodomain Proteins/metabolism ; Mice ; Proto-Oncogene Proteins/genetics/*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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  • 8
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    Molecular identification of a retinal cell type that responds to upward motion (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-03-28
    Description: The retina contains complex circuits of neurons that extract salient information from visual inputs. Signals from photoreceptors are processed by retinal interneurons, integrated by retinal ganglion cells (RGCs) and sent to the brain by RGC axons. Distinct types of RGC respond to different visual features, such as increases or decreases in light intensity (ON and OFF cells, respectively), colour or moving objects. Thus, RGCs comprise a set of parallel pathways from the eye to the brain. The identification of molecular markers for RGC subsets will facilitate attempts to correlate their structure with their function, assess their synaptic inputs and targets, and study their diversification. Here we show, by means of a transgenic marking method, that junctional adhesion molecule B (JAM-B) marks a previously unrecognized class of OFF RGCs in mice. These cells have asymmetric dendritic arbors aligned in a dorsal-to-ventral direction across the retina. Their receptive fields are also asymmetric and respond selectively to stimuli moving in a soma-to-dendrite direction; because the lens reverses the image of the world on the retina, these cells detect upward motion in the visual field. Thus, JAM-B identifies a unique population of RGCs in which structure corresponds remarkably to function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, In-Jung -- Zhang, Yifeng -- Yamagata, Masahito -- Meister, Markus -- Sanes, Joshua R -- England -- Nature. 2008 Mar 27;452(7186):478-82. doi: 10.1038/nature06739.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18368118" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomarkers/analysis ; Cell Adhesion Molecules/*metabolism ; Cell Count ; Cell Shape ; Dendrites/metabolism ; Immunoglobulins ; Mice ; Models, Neurological ; *Motion ; Photic Stimulation ; Retina/*cytology/radiation effects ; Retinal Ganglion Cells/*cytology/*metabolism/radiation effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
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    Role of Jhdm2a in regulating metabolic gene expression and obesity resistance (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-02-06
    Description: Recent studies indicate that the methylation state of histones can be dynamically regulated by histone methyltransferases and demethylases. The H3K9-specific demethylase Jhdm2a (also known as Jmjd1a and Kdm3a) has an important role in nuclear hormone receptor-mediated gene activation and male germ cell development. Through disruption of the Jhdm2a gene in mice, here we demonstrate that Jhdm2a is critically important in regulating the expression of metabolic genes. The loss of Jhdm2a function results in obesity and hyperlipidemia in mice. We provide evidence that the loss of Jhdm2a function disrupts beta-adrenergic-stimulated glycerol release and oxygen consumption in brown fat, and decreases fat oxidation and glycerol release in skeletal muscles. We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. Furthermore, we demonstrate that beta-adrenergic activation-induced binding of Jhdm2a to the PPAR responsive element (PPRE) of the Ucp1 gene not only decreases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at the PPRE, but also facilitates the recruitment of Ppargamma and Rxralpha and their co-activators Pgc1alpha (also known as Ppargc1a), CBP/p300 (Crebbp) and Src1 (Ncoa1) to the PPRE. Our studies thus demonstrate an essential role for Jhdm2a in regulating metabolic gene expression and normal weight control in mice.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085783/" 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/PMC4085783/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tateishi, Keisuke -- Okada, Yuki -- Kallin, Eric M -- Zhang, Yi -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Apr 9;458(7239):757-61. doi: 10.1038/nature07777. Epub 2009 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194461" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/metabolism ; Animals ; Cells, Cultured ; Energy Metabolism/*physiology ; Gene Expression Profiling ; *Gene Expression Regulation ; Glycerol/metabolism ; Ion Channels/metabolism ; Jumonji Domain-Containing Histone Demethylases ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondrial Proteins/metabolism ; Muscle, Skeletal/metabolism ; Obesity/*metabolism ; Oxidation-Reduction ; Oxidoreductases, N-Demethylating/*genetics/*metabolism ; Phenotype ; Receptors, Adrenergic, beta/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
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    Structural insight into the autoinhibition mechanism of AMP-activated protein kinase (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-05-29
    Description: The AMP-activated protein kinase (AMPK) is characterized by its ability to bind to AMP, which enables it to adjust enzymatic activity by sensing the cellular energy status and maintain the balance between ATP production and consumption in eukaryotic cells. It also has important roles in the regulation of cell growth and proliferation, and in the establishment and maintenance of cell polarity. These important functions have rendered AMPK an important drug target for obesity, type 2 diabetes and cancer treatments. However, the regulatory mechanism of AMPK activity by AMP binding remains unsolved. Here we report the crystal structures of an unphosphorylated fragment of the AMPK alpha-subunit (KD-AID) from Schizosaccharomyces pombe that contains both the catalytic kinase domain and an autoinhibitory domain (AID), and of a phosphorylated kinase domain from Saccharomyces cerevisiae (Snf1-pKD). The AID binds, from the 'backside', to the hinge region of its kinase domain, forming contacts with both amino-terminal and carboxy-terminal lobes. Structural analyses indicate that AID binding might constrain the mobility of helix alphaC, hence resulting in an autoinhibited KD-AID with much lower kinase activity than that of the kinase domain alone. AMP activates AMPK both allosterically and by inhibiting dephosphorylation. Further in vitro kinetic studies demonstrate that disruption of the KD-AID interface reverses the autoinhibition and these AMPK heterotrimeric mutants no longer respond to the change in AMP concentration. The structural and biochemical data have shown the primary mechanism of AMPK autoinhibition and suggest a conformational switch model for AMPK activation by AMP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Lei -- Jiao, Zhi-Hao -- Zheng, Li-Sha -- Zhang, Yuan-Yuan -- Xie, Shu-Tao -- Wang, Zhi-Xin -- Wu, Jia-Wei -- England -- Nature. 2009 Jun 25;459(7250):1146-9. doi: 10.1038/nature08075. Epub 2009 May 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MOE Key Laboratory of Bioinformatics, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19474788" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/*chemistry/*metabolism ; Adenosine Monophosphate/metabolism ; Amino Acid Sequence ; Animals ; *Models, Molecular ; Molecular Sequence Data ; Mutation ; Phosphorylation ; Protein Structure, Tertiary ; Rats ; Saccharomyces cerevisiae/*enzymology ; Schizosaccharomyces/*enzymology ; Sequence Alignment
    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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