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Mitochondrial defects trigger proliferation of neighbouring cells via a senescence-associated secretory phenotype in Drosophila

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  • Mai Nakamura

    (Laboratory of Genetics, Graduate School of Biostudies, Kyoto University
    Kobe University Graduate School of Medicine)

  • Shizue Ohsawa

    (Laboratory of Genetics, Graduate School of Biostudies, Kyoto University)

  • Tatsushi Igaki

    (Laboratory of Genetics, Graduate School of Biostudies, Kyoto University
    PRESTO, Japan Science and Technology Agency (JST))

Abstract

Cell–cell interactions play important roles in epithelial tumorigenesis. Here we show in Drosophila imaginal epithelium that Ras activation and mitochondrial dysfunction, frequent alterations in cancers, cause cellular senescence and senescence-associated secretory phenotype (SASP), which leads to overgrowth of neighbouring tissue. Ras-activated cells express several hallmarks of cellular senescence such as elevation of senescence-associated β-galactosidase activity, upregulation of the Cdk inhibitor Dacapo, heterochromatinization and cellular hypertrophy. Strikingly, defects in mitochondrial function cause Ras-activated cells to undergo DNA damage response, cell cycle arrest and thereby induce SASP, exhibiting full aspects of cellular senescence. Mechanistically, mitochondrial defects in conjunction with Ras cause production of reactive oxygen species, downregulation of CycE activity and activation of p53, which cooperate together to trigger a cell cycle arrest-Jun N-terminal kinase (JNK) feedback loop that amplifies JNK activation, leading to upregulation of the inflammatory cytokine Unpaired. Our data suggest that mitochondrial defects promote Ras-induced cellular senescence and thereby contribute to tumour progression through SASP.

Suggested Citation

  • Mai Nakamura & Shizue Ohsawa & Tatsushi Igaki, 2014. "Mitochondrial defects trigger proliferation of neighbouring cells via a senescence-associated secretory phenotype in Drosophila," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6264
    DOI: 10.1038/ncomms6264
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