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  • 1
    Publication Date: 2014-02-21
    Description: Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paolino, Magdalena -- Choidas, Axel -- Wallner, Stephanie -- Pranjic, Blanka -- Uribesalgo, Iris -- Loeser, Stefanie -- Jamieson, Amanda M -- Langdon, Wallace Y -- Ikeda, Fumiyo -- Fededa, Juan Pablo -- Cronin, Shane J -- Nitsch, Roberto -- Schultz-Fademrecht, Carsten -- Eickhoff, Jan -- Menninger, Sascha -- Unger, Anke -- Torka, Robert -- Gruber, Thomas -- Hinterleitner, Reinhard -- Baier, Gottfried -- Wolf, Dominik -- Ullrich, Axel -- Klebl, Bert M -- Penninger, Josef M -- W 1101/Austrian Science Fund FWF/Austria -- England -- Nature. 2014 Mar 27;507(7493):508-12. doi: 10.1038/nature12998. Epub 2014 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria. ; Lead Discovery Center GmbH, D-44227 Dortmund, Germany. ; Medical University Innsbruck, 6020 Innsbruck, Austria. ; Department of Microbiology and Immunology, Brown University, Providence, Rhode Island 02912, USA. ; School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Perth, Australia. ; Max-Planck, Institute for Biochemistry, Department of Molecular Biology, D-82152 Martinsried, Germany. ; 1] Medical University Innsbruck, 6020 Innsbruck, Austria [2] Internal Medicine III, University Hospital Bonn, 53127 Bonn, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553136" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/deficiency/genetics/*metabolism ; Animals ; Anticoagulants/pharmacology/therapeutic use ; Female ; Killer Cells, Natural/drug effects/*immunology/metabolism ; Male ; Mammary Neoplasms, Experimental/drug therapy/genetics/immunology/*pathology ; Melanoma, Experimental/drug therapy/genetics/immunology/*pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplasm Metastasis/drug therapy/*immunology/prevention & control ; Proto-Oncogene Proteins/antagonists & inhibitors/metabolism ; Proto-Oncogene Proteins c-cbl/deficiency/genetics/*metabolism ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors/*metabolism ; Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism ; Ubiquitination ; Warfarin/pharmacology/therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-07-28
    Description: Malnutrition affects up to one billion people in the world and is a major cause of mortality. In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death. The mechanisms by which unbalanced dietary nutrients affect intestinal homeostasis are largely unknown. Here we report that deficiency in murine angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (Ace2), which encodes a key regulatory enzyme of the renin-angiotensin system (RAS), results in highly increased susceptibility to intestinal inflammation induced by epithelial damage. The RAS is known to be involved in acute lung failure, cardiovascular functions and SARS infections. Mechanistically, ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. Transplantation of the altered microbiota from Ace2 mutant mice into germ-free wild-type hosts was able to transmit the increased propensity to develop severe colitis. ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan. Our results identify ACE2 as a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis. These results provide a molecular explanation for how amino acid malnutrition can cause intestinal inflammation and diarrhoea.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hashimoto, Tatsuo -- Perlot, Thomas -- Rehman, Ateequr -- Trichereau, Jean -- Ishiguro, Hiroaki -- Paolino, Magdalena -- Sigl, Verena -- Hanada, Toshikatsu -- Hanada, Reiko -- Lipinski, Simone -- Wild, Birgit -- Camargo, Simone M R -- Singer, Dustin -- Richter, Andreas -- Kuba, Keiji -- Fukamizu, Akiyoshi -- Schreiber, Stefan -- Clevers, Hans -- Verrey, Francois -- Rosenstiel, Philip -- Penninger, Josef M -- England -- Nature. 2012 Jul 25;487(7408):477-81. doi: 10.1038/nature11228.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22837003" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biocatalysis ; Colitis/drug therapy/*etiology/*microbiology/pathology ; Dextran Sulfate ; Diarrhea/complications ; Dietary Proteins/metabolism/pharmacology ; Female ; Gene Deletion ; Genetic Predisposition to Disease ; Germ-Free Life ; Homeostasis ; Immunity, Innate ; Intestines/*microbiology/pathology ; Male ; Malnutrition/*complications/metabolism ; *Metagenome ; Mice ; Models, Biological ; Niacinamide/metabolism/pharmacology/therapeutic use ; Peptidyl-Dipeptidase A/deficiency/genetics/*metabolism ; Renin-Angiotensin System/physiology ; TOR Serine-Threonine Kinases/metabolism ; Trinitrobenzenesulfonic Acid ; Tryptophan/*metabolism/pharmacology/therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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