title: Screening of a kinase library reveals novel pro-senescence kinases and their common NF-κB-dependent transcriptional program.
abstract: 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-κB-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-κB, 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.
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69373 Lyon, France.|CNRS UMR 5286, F-69373 Lyon, France.|Centre Léon Bérard, F-69373 Lyon, France.|Université de Lyon, F-69373 Lyon, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Ferrand
authors.affiliation: Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Kirsh
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69373 Lyon, France.|CNRS UMR 5286, F-69373 Lyon, France.|Centre Léon Bérard, F-69373 Lyon, France.|Université de Lyon, F-69373 Lyon, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Griveau
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69373 Lyon, France.|CNRS UMR 5286, F-69373 Lyon, France.|Centre Léon Bérard, F-69373 Lyon, France.|Université de Lyon, F-69373 Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Vindrieux
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69373 Lyon, France.|CNRS UMR 5286, F-69373 Lyon, France.|Centre Léon Bérard, F-69373 Lyon, France.|Université de Lyon, F-69373 Lyon, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Martin
authors.affiliation: Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France.
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Defossez
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69373 Lyon, France.|CNRS UMR 5286, F-69373 Lyon, France.|Centre Léon Bérard, F-69373 Lyon, France.|Université de Lyon, F-69373 Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Bernard
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence; D019942:Genes, p16; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000502:physiology; D015398:Signal Transduction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D016328:NF-kappa B; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases
keywords: NF-κB; kinases; screen; senescence; signaling