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  • GENE-EXPRESSION  (2)
  • Mice, Knockout
  • Corticotropin-Releasing Hormone/metabolism
Keywords
Years
  • 1
    Keywords: APOPTOSIS ; CANCER ; GROWTH ; GENE-EXPRESSION ; STEM-CELLS ; CENTRAL-NERVOUS-SYSTEM ; neuroblastoma ; N-MYC ; BRAIN-TUMORS ; TUMOR-SUPPRESSOR
    Abstract: Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option. (c) 2014 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 25348795
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  • 2
    Keywords: EXPRESSION ; SURVIVAL ; CELL ; Germany ; human ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; PROTEINS ; TISSUE ; HEART ; MICE ; INFECTION ; MECHANISM ; REDUCTION ; TRANSPLANTATION ; DOMAIN ; mechanisms ; T cell ; T-CELL ; knockout ; IDENTIFICATION ; gene expression ; affymetrix ; DAMAGE ; WILD-TYPE ; arteries ; WALL ; REJECTION ; ARTERY ; METALLOPROTEASE ; RECEPTORS ; MICROARRAY ANALYSIS ; chemokine ; ARCHITECTURE ; MATRIX ; INFILTRATION ; MATRIX METALLOPROTEINASES ; CCR5 ; ALLOGRAFT-REJECTION ; CHEMOKINE RECEPTORS
    Abstract: Experimental and human organ transplant studies suggest an important role for chemokine (C-C-motif) receptor-5 (CCR5) in the development of acute and chronic allograft rejection. Because early transplant damage can predispose allografts to chronic dysfunction, we sought to identify potential pathophysiologic mechanisms leading to allograft damage by using wild-type and Ccr5-deficient mice as recipients of fully MHC-mismatched heart and carotid-artery allografts. Gene expression in rejecting heart allografts was analyzed 2 and 6 days after transplantation using Affymetrix GeneChips. Microarray analysis led to identification of four metalloproteinase genes [matrix metalloproteinase (Mmp)3, Mmp12, Mmp13 and a disintegrin and metalloprotease domain (Adam)8] with significantly diminished intragraft mRNA expression in Ccr5-deficient mice at day 6. Accordingly, allografts from Ccr5-deficient mice showed less tissue remodeling and hence better preservation of the myocardial architecture compared with allografts from wild-type recipients. Moreover, survival of cardiac allografts was significantly increased in Ccr5-deficient mice. Carotid artery allografts from Ccr5-deficient recipients showed better tissue preservation, and significant reduction of neointima formation and CD3(+) T cell infiltration. Ccr5 appears to play an important role in transplant-associated arteriosclerosis that may involve metalloproteinase-mediated vessel wall remodeling. We conclude that early tissue remodeling may be a critical feature in the predisposition of allografts to the development of chronic dysfunction
    Type of Publication: Journal article published
    PubMed ID: 15307189
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  • 3
    Publication Date: 2011-09-03
    Description: The corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioral adaptation to stress and is causally linked to emotional disorders. Using neurochemical and genetic tools, we determined that CRHR1 is expressed in forebrain glutamatergic and gamma-aminobutyric acid-containing (GABAergic) neurons as well as in midbrain dopaminergic neurons. Via specific CRHR1 deletions in glutamatergic, GABAergic, dopaminergic, and serotonergic cells, we found that the lack of CRHR1 in forebrain glutamatergic circuits reduces anxiety and impairs neurotransmission in the amygdala and hippocampus. Selective deletion of CRHR1 in midbrain dopaminergic neurons increases anxiety-like behavior and reduces dopamine release in the prefrontal cortex. These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Refojo, Damian -- Schweizer, Martin -- Kuehne, Claudia -- Ehrenberg, Stefanie -- Thoeringer, Christoph -- Vogl, Annette M -- Dedic, Nina -- Schumacher, Marion -- von Wolff, Gregor -- Avrabos, Charilaos -- Touma, Chadi -- Engblom, David -- Schutz, Gunther -- Nave, Klaus-Armin -- Eder, Matthias -- Wotjak, Carsten T -- Sillaber, Inge -- Holsboer, Florian -- Wurst, Wolfgang -- Deussing, Jan M -- New York, N.Y. -- Science. 2011 Sep 30;333(6051):1903-7. doi: 10.1126/science.1202107. Epub 2011 Sep 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute of Psychiatry, Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21885734" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/metabolism ; Animals ; *Anxiety ; Behavior, Animal ; Corticotropin-Releasing Hormone/metabolism ; Dopamine/*metabolism ; Fear ; Glutamic Acid/*metabolism ; Hippocampus/metabolism ; Male ; Memory ; Mesencephalon ; Mice ; Mice, Knockout ; Motor Activity ; Neurons/*metabolism ; Prefrontal Cortex/metabolism ; Prosencephalon/cytology/metabolism ; Receptors, Corticotropin-Releasing Hormone/antagonists & ; inhibitors/genetics/*metabolism ; Synaptic Transmission ; Ventral Tegmental Area/metabolism ; gamma-Aminobutyric Acid/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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