title: Endoplasmic reticulum stress sensitizes cells to DNA damage-induced apoptosis through p53-dependent suppression of p21(CDKN1A).
abstract: Endoplasmic reticulum (ER) stress occurs in poorly perfused tissues and activates the p53 isoform p53/47 to promote G2 arrest via 14-3-3σ. This contrasts with the p21(CDKN1A)-dependent G1 arrest caused by p53 following DNA damage. It is not known how cells respond to conditions when both pathways are activated. Here we show that p53/47 prevents p53-induced p21 transcription during ER stress and that both isoforms repress p21 mRNA translation. This prevents p21 from promoting COP1-mediated 14-3-3σ degradation and leads to G2 arrest. DNA damage does not result in p53-dependent induction of p21 during ER stress and instead results in an increase in p53-induced apoptosis. This illustrates how p53 isoforms target an intrinsic balance between the G1 and G2 checkpoints for cell cycle coordination and demonstrates an ER stress-dependent p53 pathway that suppresses p21 and lowers the apoptotic threshold to genotoxic drugs.
authors.affiliation: Equipe Labellisée Ligue Contre le Cancer, Université Paris 7, INSERM UMR 1162, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Coraline
authors.initials: C
authors.lastname: Mlynarczyk
authors.affiliation: 1] Equipe Labellisée Ligue Contre le Cancer, Université Paris 7, INSERM UMR 1162, 27 rue Juliette Dodu, 75010 Paris, France [2] RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic.
authors.forename: Robin
authors.initials: R
authors.lastname: Fåhraeus
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress; D005095:Exoribonucleases / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C471981:COP1 protein, human; D044767:Ubiquitin-Protein Ligases; D005095:Exoribonucleases; C413442:SFN protein, human