title: Escape from p21-mediated oncogene-induced senescence leads to cell dedifferentiation and dependence on anti-apoptotic Bcl-xL and MCL1 proteins.
abstract: Oncogene-induced senescence (OIS) is a tumor suppressor response that induces permanent cell cycle arrest in response to oncogenic signaling. Through the combined activation of the p53-p21 and p16-Rb suppressor pathways, OIS leads to the transcriptional repression of proliferative genes. Although this protective mechanism has been essentially described in primary cells, we surprisingly observed in this study that the OIS program is conserved in established colorectal cell lines. In response to the RAS oncogene and despite the inactivation of p53 and p16(INK4), HT29 cells enter senescence, up-regulate p21(WAF1), and induce senescence-associated heterochromatin foci formation. The same effect was observed in response to B-RAF(v600E) in LS174T cells. We also observed that p21(WAF1) prevents the expression of the CDC25A and PLK1 genes to induce cell cycle arrest. Using ChIP and luciferase experiments, we have observed that p21(WAF1) binds to the PLK1 promoter to induce its down-regulation during OIS induction. Following 4-5 weeks, several clones were able to resume proliferation and escape this tumor suppressor pathway. Tumor progression was associated with p21(WAF1) down-regulation and CDC25A and PLK1 reexpression. In addition, OIS and p21(WAF1) escape was associated with an increase in DNA damage, an induction of the epithelial-mesenchymal transition program, and an increase in the proportion of cells expressing the CD24(low)/CD44(high) phenotype. Results also indicate that malignant cells having escaped OIS rely on survival pathways induced by Bcl-xL/MCL1 signaling. In light of these observations, it appears that the transcriptional functions of p21(WAF1) are active during OIS and that the inactivation of this protein is associated with cell dedifferentiation and enhanced survival.
authors.affiliation: Cancer Center Paul Papin, INSERM U892, 49033 Angers, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: de Carné Trécesson
authors.forename: Yannis
authors.initials: Y
authors.lastname: Guillemin
authors.forename: Audrey
authors.initials: A
authors.lastname: Bélanger
authors.forename: Anne-Charlotte
authors.initials: AC
authors.lastname: Bernard
authors.forename: Laurence
authors.initials: L
authors.lastname: Preisser
authors.forename: Elisa
authors.initials: E
authors.lastname: Ravon
authors.forename: Erick
authors.initials: E
authors.lastname: Gamelin
authors.forename: Philippe
authors.initials: P
authors.lastname: Juin
authors.forename: Benjamin
authors.initials: B
authors.lastname: Barré
authors.forename: Olivier
authors.initials: O
authors.lastname: Coqueret
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D016922:Cellular Senescence; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006570:Heterochromatin; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015689:Oncogene Protein p21(ras); D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D020687:cdc25 Phosphatases; D000097869:Polo-Like Kinase 1; C494811:BCL2L1 protein, human; C493956:CDKN1A protein, human; C495901:TP53 protein, human; C482119:BRAF protein, human; C517004:CDC25A protein, human