期刊
NATURE COMMUNICATIONS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms6264
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- MEXT
- Japan Society for the Promotion of Science for Young Scientists
- Japan Science and Technology Agency
- Global COE program for Global Center for Education and Research in Integrative Membrane Biology
- Molecular Biology Society of Japan for Young Scientist
- Novartis Foundation for the Promotion of Science
- Nakajima Foundation
- Inoue Science Research Award
- Takeda Science Foundation
- Senri Life Science Foundation
- Kao Function for Art and Science
- Shiseido Female Researcher Science grant
- Uehara Memorial Foundation
- Suzuken Memorial Foundation
- Inamori Foundation
- Human Frontier Science Program Career Development Award
- Grants-in-Aid for Scientific Research [26114002, 25640064] Funding Source: KAKEN
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 beta-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 cyclearrest-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.
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