title: Extracellular Reactive Oxygen Species Drive Apoptosis-Induced Proliferation via Drosophila Macrophages.
abstract: Apoptosis-induced proliferation (AiP) is a compensatory mechanism to maintain tissue size and morphology following unexpected cell loss during normal development, and may also be a contributing factor to cancer and drug resistance. In apoptotic cells, caspase-initiated signaling cascades lead to the downstream production of mitogenic factors and the proliferation of neighboring surviving cells. In epithelial cells of Drosophila imaginal discs, the Caspase-9 ortholog Dronc drives AiP via activation of Jun N-terminal kinase (JNK); however, the specific mechanisms of JNK activation remain unknown. Here we show that caspase-induced activation of JNK during AiP depends on an inflammatory response. This is mediated by extracellular reactive oxygen species (ROSs) generated by the NADPH oxidase Duox in epithelial disc cells. Extracellular ROSs activate Drosophila macrophages (hemocytes), which in turn trigger JNK activity in epithelial cells by signaling through the tumor necrosis factor (TNF) ortholog Eiger. We propose that in an immortalized ("undead") model of AiP, signaling back and forth between epithelial disc cells and hemocytes by extracellular ROSs and TNF/Eiger drives overgrowth of the disc epithelium. These data illustrate a bidirectional cell-cell communication pathway with implication for tissue repair, regeneration, and cancer.
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, LRB 416, Worcester, MA 01605, USA.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Fogarty
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, LRB 416, Worcester, MA 01605, USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Diwanji
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, LRB 416, Worcester, MA 01605, USA.
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Lindblad
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, LRB 416, Worcester, MA 01605, USA.
authors.forename: Meghana
authors.initials: M
authors.lastname: Tare
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, LRB 416, Worcester, MA 01605, USA.
authors.forename: Alla
authors.initials: A
authors.lastname: Amcheslavsky
authors.affiliation: Broad Center, Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Makhijani
authors.affiliation: Broad Center, Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA.
authors.forename: Katja
authors.initials: K
authors.lastname: Brückner
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Yun
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, LRB 416, Worcester, MA 01605, USA. Electronic address: andreas.bergmann@umassmed.edu.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergmann
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007814:Larva; D008264:Macrophages / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases