Inactivation of the p53 protein in cell lines derived from human esophageal cancers.
Alteration of the p53 gene is thought to be important in the early stages of human esophageal cancers, but how this confers a selective advantage to esophageal cancer cells is unknown. In this report, we analyzed 9 cell lines derived from human esophageal cancers (TE-1, TE-3, TE-6, TE-7, TE-9, TE-10, TE-11, TE-13 and TE-15) for mutations in the p53 sequence, p53 protein expression and p53 protein DNA-binding activity. The cell lines could be grouped in 3 categories, including (1) cell lines with mis-sense mutations in the coding sequence and accumulation of mutant proteins (TE-1, TE-6, TE-10 and TE-11); (2) cell lines expressing truncated forms of p53 as a result of frameshift (TE-9) or splice-site (TE-15) mutations; and (3) cell lines with wild-type p53 sequences but with impaired expression of p53 mRNA and protein, suggesting that p53 is inactivated by transcriptional repression (TE-3, TE-7 and TE-13). With the exception of TE-1, none of the cell lines exhibited p53-DNA-binding activity. In TE-1, a mutation at codon 272 (methionine to valine) generated a protein that retains basal DNA-binding activity, but that was not activated in response to DNA damage, suggesting that this mutation prevented p53 induction by genotoxic stress. Thus, p53 activity was impaired in all esophageal cell lines, including those containing wild-type p53 sequences.
Barnas
C
C
International Agency for Research on Cancer, Unit of Mechanisms of Carcinogenesis, Lyon, France.
Martel-Planche
G
G
Furukawa
Y
Y
Hollstein
M
M
Montesano
R
R
Hainaut
P
P
D001483:Base Sequence; D015153:Blotting, Western; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004938:Esophageal Neoplasms / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*
D009153:Mutagens; D016877:Oxidants; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004247:DNA; D008741:Methyl Methanesulfonate; D006861:Hydrogen Peroxide