title: Tumor suppression in mice lacking GABARAP, an Atg8/LC3 family member implicated in autophagy, is associated with alterations in cytokine secretion and cell death.
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-1β, 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.
authors.affiliation: Institute of Pathology, University Hospital - Friedrich Schiller University Jena, Ziegelmühlenweg 1, Jena D-07743, Germany.|Iraqi Centre for Cancer and Medical Genetics Research, Al-Mustansiriya University, Baghdad, Iraq.
authors.forename: F S
authors.initials: FS
authors.lastname: Salah
authors.affiliation: Institute of Physiology 1, University Hospital - Friedrich Schiller University Jena, Teichgraben 8, Jena D-07743, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ebbinghaus
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI), Beutenbergstrasse 11, Jena D-07745, Germany.|Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Erlanger Allee 101, Jena D-07747, Germany.
authors.forename: V Y
authors.initials: VY
authors.lastname: Muley
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, Jena D-07745, Germany.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Iraqi Centre for Cancer and Medical Genetics Research, Al-Mustansiriya University, Baghdad, Iraq.
authors.forename: K R D
authors.initials: KR
authors.lastname: Al-Saadi
authors.affiliation: Institute of Pathology, University Medicine Berlin, Campus Charité Mitte, Berlin D-10098, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pacyna-Gengelbach
authors.affiliation: Department of Neurochemistry, Max-Planck Institute for Brain Research, Deutschordenstrasse 46, Frankfurt D-60528, Germany.
authors.forename: G A
authors.initials: GA
authors.lastname: O'Sullivan
authors.affiliation: Department of Neurochemistry, Max-Planck Institute for Brain Research, Deutschordenstrasse 46, Frankfurt D-60528, Germany.|Max-Planck Institute for Medical Research, Jahnstrasse 29, Heidelberg D-69120, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Betz
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI), Beutenbergstrasse 11, Jena D-07745, Germany.|Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Erlanger Allee 101, Jena D-07747, Germany.
authors.forename: R
authors.initials: R
authors.lastname: König
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, Jena D-07745, Germany.|Faculty of Biology and Pharmacy, Friedrich Schiller University Jena, Bachstrasse 18k, Jena D-07743, Germany.
authors.forename: Z-Q
authors.initials: ZQ
authors.lastname: Wang
authors.affiliation: Institute of Pathology, University Hospital - Friedrich Schiller University Jena, Ziegelmühlenweg 1, Jena D-07743, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Bräuer
authors.affiliation: Institute of Pathology, University Hospital - Friedrich Schiller University Jena, Ziegelmühlenweg 1, Jena D-07743, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Petersen
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000187:drug effects; D000071190:Autophagy-Related Protein 8 Family / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D008070:Lipopolysaccharides / Q000633:toxicity; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000097:blood
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000071190:Autophagy-Related Protein 8 Family; D016207:Cytokines; D003598:Cytoskeletal Proteins; D044783:F-Box Proteins; C480861:GABARAP protein, mouse; D008070:Lipopolysaccharides; C480860:Map1lc3b protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D053773:Transforming Growth Factor beta1; C528956:XAF1 protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene