Journal
AGING-US
Volume 7, Issue 11, Pages 986-1003Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.100845
Keywords
senescence; kinases; screen; signaling; NF-kappa B
Categories
Funding
- AAP Epigenome et Cancer of the Plan Cancer [P030830]
- Fondation ARC
- [ANR-11-LABX-0071]
- [ANR-11-IDEX-0005-01]
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Cellular senescence results in proliferation arrest and acquisition of hallmarks such as the Senescence-Associated Secretory Phenotype (SASP). Senescence is involved in regulating numerous physio-pathological responses, including embryonic development, cancer, and several aging-related diseases. Only a few kinases, centered on the RAS signaling pathway, have been identified as inducing premature senescence. About possible other senescence-regulating kinases and signaling pathways, practically little is known. By screening a library of activated kinases, we identified 33 kinases whose constitutive expression decreases cell proliferation and induces expression of senescence markers; p16 and SASP components. Focusing on some kinases showing the strongest pro-senescence effects, we observed that they all induce expression of SASP-component genes through activation of an NF-kappa B-dependent transcriptional program. Furthermore, inhibition of the p53 or Rb pathway failed to prevent the SASP-inducing effect of pro-senescence kinases. Inhibition of the NF-kappa B, p53, or Rb pathway proved insufficient to prevent kinase-triggered cell cycle arrest. We have thus identified a repertoire of novel pro-senescence kinases and pathways. These results will open new perspectives in the understanding on the role of cellular senescence in various physio-pathological responses.
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