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      Tumor suppression in mice lacking GABARAP, an Atg8/LC3 family member implicated in autophagy, is associated with alterations in cytokine secretion and cell death

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          Abstract

          GABARAP belongs to an evolutionary highly conserved gene family that has a fundamental role in autophagy. There is ample evidence for a crosstalk between autophagy and apoptosis as well as the immune response. However, the molecular details for these interactions are not fully characterized. Here, we report that the ablation of murine GABARAP, a member of the Atg8/LC3 family that is central to autophagosome formation, suppresses the incidence of tumor formation mediated by the carcinogen DMBA and results in an enhancement of the immune response through increased secretion of IL-1 β, IL-6, IL-2 and IFN- γ from stimulated macrophages and lymphocytes. In contrast, TGF- β1 was significantly reduced in the serum of these knockout mice. Further, DMBA treatment of these GABARAP knockout mice reduced the cellularity of the spleen and the growth of mammary glands through the induction of apoptosis. Gene expression profiling of mammary glands revealed significantly elevated levels of Xaf1, an apoptotic inducer and tumor-suppressor gene, in knockout mice. Furthermore, DMBA treatment triggered the upregulation of pro-apoptotic (Bid, Apaf1, Bax), cell death (Tnfrsf10b, Ripk1) and cell cycle inhibitor (Cdkn1a, Cdkn2c) genes in the mammary glands. Finally, tumor growth of B16 melanoma cells after subcutaneous inoculation was inhibited in GABARAP-deficient mice. Together, these data provide strong evidence for the involvement of GABARAP in tumorigenesis in vivo by delaying cell death and its associated immune-related response.

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          Most cited references32

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          Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion.

          Autophagy involves de novo formation of double membrane-bound structures called autophagosomes, which engulf material to be degraded in lytic compartments. Atg8 is a ubiquitin-like protein required for this process in Saccharomyces cerevisiae that can be conjugated to the lipid phosphatidylethanolamine by a ubiquitin-like system. Here, we show using an in vitro system that Atg8 mediates the tethering and hemifusion of membranes, which are evoked by the lipidation of the protein and reversibly modulated by the deconjugation enzyme Atg4. Mutational analyses suggest that membrane tethering and hemifusion observed in vitro represent an authentic function of Atg8 in autophagosome formation in vivo. In addition, electron microscopic analyses indicate that these functions of Atg8 are involved in the expansion of autophagosomal membranes. Our results provide further insights into the mechanisms underlying the unique membrane dynamics of autophagy and also indicate the functional versatility of ubiquitin-like proteins.
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            Ubiquitin and ubiquitin-like proteins as multifunctional signals.

            Protein ubiquitylation is a recognized signal for protein degradation. However, it is increasingly realized that ubiquitin conjugation to proteins can be used for many other purposes. Furthermore, there are many ubiquitin-like proteins that control the activities of proteins. The central structural element of these post-translational modifications is the ubiquitin superfold. A common ancestor based on this superfold has evolved to give various proteins that are involved in diverse activities in the cell.
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              Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death.

              To delineate specific developmental roles of transforming growth factor beta 1 (TGF-beta 1) we have disrupted its cognate gene in mouse embryonic stem cells by homologous recombination to generate TGF-beta 1 null mice. These mice do not produce detectable amounts of either TGF-beta 1 RNA or protein. After normal growth for the first 2 weeks they develop a rapid wasting syndrome and die by 3-4 weeks of age. Pathological examination revealed an excessive inflammatory response with massive infiltration of lymphocytes and macrophages in many organs, but primarily in heart and lungs. Many lesions resembled those found in autoimmune disorders, graft-vs.-host disease, or certain viral diseases. This phenotype suggests a prominent role for TGF-beta 1 in homeostatic regulation of immune cell proliferation and extravasation into tissues.
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                Author and article information

                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                April 2016
                28 April 2016
                1 April 2016
                : 7
                : 4
                : e2205
                Affiliations
                [1 ]Institute of Pathology, University Hospital – Friedrich Schiller University Jena , Ziegelmühlenweg 1, Jena D-07743, Germany
                [2 ]Iraqi Centre for Cancer and Medical Genetics Research, Al-Mustansiriya University , Baghdad, Iraq
                [3 ]Institute of Physiology 1, University Hospital – Friedrich Schiller University Jena , Teichgraben 8, Jena D-07743, Germany
                [4 ]Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI) , Beutenbergstrasse 11, Jena D-07745, Germany
                [5 ]Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital , Erlanger Allee 101, Jena D-07747, Germany
                [6 ]Leibniz Institute for Age Research – Fritz Lipmann Institute (FLI) , Beutenbergstrasse 11, Jena D-07745, Germany
                [7 ]Institute of Pathology, University Medicine Berlin, Campus Charité Mitte , Berlin D-10098, Germany
                [8 ]Department of Neurochemistry, Max-Planck Institute for Brain Research , Deutschordenstrasse 46, Frankfurt D-60528, Germany
                [9 ]Max-Planck Institute for Medical Research , Jahnstrasse 29, Heidelberg D-69120, Germany
                [10 ]Faculty of Biology and Pharmacy, Friedrich Schiller University Jena , Bachstrasse 18k, Jena D-07743, Germany
                Author notes
                [* ]Institute of Pathology, University Hospital – Friedrich Schiller University Jena , Ziegelmühlenweg 1, Jena D-07740, Germany. Tel: +49 3641 9 33 120; Fax: +49 3641 9 33 111; E-mail: Iver.Petersen@ 123456med.uni-jena.de
                Article
                cddis201693
                10.1038/cddis.2016.93
                4855672
                27124579
                892cddd8-acfc-4b36-9894-1d296551635f
                Copyright © 2016 Macmillan Publishers Limited

                Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 09 August 2015
                : 11 March 2016
                : 15 March 2016
                Categories
                Original Article

                Cell biology
                Cell biology

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