Document Detail


Escape from p21-mediated oncogene-induced senescence leads to cell dedifferentiation and dependence on anti-apoptotic Bcl-xL and MCL1 proteins.
MedLine Citation:
PMID:  21292770     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Sophie de Carné Trécesson; Yannis Guillemin; Audrey Bélanger; Anne-Charlotte Bernard; Laurence Preisser; Elisa Ravon; Erick Gamelin; Philippe Juin; Benjamin Barré; Olivier Coqueret
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-02-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-04-11     Completed Date:  2011-06-28     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  12825-38     Citation Subset:  IM    
Affiliation:
Cancer Center Paul Papin, INSERM U892, 49033 Angers, France.
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MeSH Terms
Descriptor/Qualifier:
Cell Aging*
Cell Cycle Proteins / genetics,  metabolism
Cell Dedifferentiation*
Cell Line, Tumor
Cell Proliferation
Cell Survival / genetics
Cyclin-Dependent Kinase Inhibitor Proteins / genetics,  metabolism
Cyclin-Dependent Kinase Inhibitor p21 / genetics,  metabolism*
Heterochromatin / genetics,  metabolism
Humans
Mutation, Missense
Oncogene Protein p21(ras) / genetics,  metabolism
Protein-Serine-Threonine Kinases / genetics,  metabolism
Proto-Oncogene Proteins / genetics,  metabolism
Proto-Oncogene Proteins B-raf / genetics,  metabolism
Proto-Oncogene Proteins c-bcl-2 / genetics,  metabolism*
Signal Transduction / genetics
Time Factors
Transcription, Genetic / genetics
Tumor Suppressor Protein p53 / genetics,  metabolism
Up-Regulation / genetics
bcl-X Protein / genetics,  metabolism*
cdc25 Phosphatases / genetics,  metabolism
Chemical
Reg. No./Substance:
0/BCL2L1 protein, human; 0/CDKN1A protein, human; 0/Cell Cycle Proteins; 0/Cyclin-Dependent Kinase Inhibitor Proteins; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Heterochromatin; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 0/bcl-X Protein; 0/myeloid cell leukemia sequence 1 protein; EC 2.7.11.1/BRAF protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins B-raf; EC 2.7.11.1/polo-like kinase 1; EC 3.1.3.48/CDC25A protein, human; EC 3.1.3.48/cdc25 Phosphatases; EC 3.6.5.2/Oncogene Protein p21(ras)
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