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  • 1
    Publication Date: 2015-07-15
    Description: Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. Here we show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins--MITF, TFE3 and TFEB--are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. These results identify the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perera, Rushika M -- Stoykova, Svetlana -- Nicolay, Brandon N -- Ross, Kenneth N -- Fitamant, Julien -- Boukhali, Myriam -- Lengrand, Justine -- Deshpande, Vikram -- Selig, Martin K -- Ferrone, Cristina R -- Settleman, Jeff -- Stephanopoulos, Gregory -- Dyson, Nicholas J -- Zoncu, Roberto -- Ramaswamy, Sridhar -- Haas, Wilhelm -- Bardeesy, Nabeel -- DP2 CA195761/CA/NCI NIH HHS/ -- P01 CA117969/CA/NCI NIH HHS/ -- P01 CA117969-07/CA/NCI NIH HHS/ -- P50CA1270003/CA/NCI NIH HHS/ -- R01 CA133557-05/CA/NCI NIH HHS/ -- England -- Nature. 2015 Aug 20;524(7565):361-5. doi: 10.1038/nature14587. Epub 2015 Jul 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA. ; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26168401" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Amino Acids/metabolism ; Animals ; Autophagy/*genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Carcinoma, Pancreatic Ductal/*genetics/*metabolism/pathology ; Cell Line, Tumor ; Energy Metabolism ; Female ; *Gene Expression Regulation, Neoplastic ; Heterografts ; Homeostasis ; Humans ; Lysosomes/genetics/*metabolism ; Mice ; Microphthalmia-Associated Transcription Factor/metabolism ; Neoplasm Transplantation ; Pancreatic Neoplasms/genetics/*metabolism/*pathology ; Transcription Factors/*metabolism ; Transcription, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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