title: Decreased translation of p21waf1 mRNA causes attenuated p53 signaling in some p53 wild-type tumors.
abstract: DNA damage induces cell cycle arrest through both Chk1 and the p53 tumor suppressor protein, the latter arresting cells through induction of p21(waf1) protein. Arrest permits cells to repair the damage and recover. The frequent loss of p53 in tumor cells makes them more dependent on Chk1 for arrest and survival. However, some p53 wild type tumor cell lines, such as HCT116 and U2OS, are also sensitive to inhibition of Chk1 due to attenuated p21(waf1) induction upon DNA damage. The purpose of this study is to determine the cause of this attenuated p21(waf1) protein induction. We find that neither the induction of p21(waf1) mRNA nor protein half-life is sufficient to explain the low p21(waf1) protein levels in HCT116 and U2OS cells. The induced mRNA associates with polysomes but little protein is made suggesting these two cell lines have a reduced rate of p21(waf1) mRNA translation. This represents a novel mechanism for disruption of the p53-p21(waf1) pathway as currently known mechanisms involve either mutation of p53 or reduction of p53 protein levels. As a consequence, this attenuated p21(waf1) expression may render some p53 wild type tumors sensitive to a combination of DNA damage plus checkpoint inhibition.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School and Norris Cotton Cancer Center, Lebanon, NH, USA.
authors.forename: Li-Ju
authors.initials: LJ
authors.lastname: Chang
authors.forename: Alan
authors.initials: A
authors.lastname: Eastman
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D059447:Cell Cycle Checkpoints; D000071877:Checkpoint Kinase 1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006207:Half-Life; D006801:Humans; D000077146:Irinotecan; D007700:Kinetics; D010766:Phosphorylation; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C559815:MK-8776; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D002166:Camptothecin