Evasion of p53-mediated growth control occurs by three alternative mechanisms in transformed thyroid epithelial cells.
Using the thyroid as a model of multistep epithelial tumorigenesis, we have used representative cell lines to correlate the degree of malignant transformation with the functional status of p53 and the integrity of cell-cycle check-points. Three distinct phenotypes were observed: Type I lines, derived from poorly-differentiated human thyroid cancers, expressed high levels of mutant p53 protein; Type II, also poorly-differentiated but derived from rat, showed over-expression of wild-type (wt) p53 with marked cell-cell heterogeneity: Type III, from well-differentiated human cancers, contained uniformly low levels of wt p53. All cell lines containing wt p53 retained a near-normal induction of p53 by DNA damage. However, the ability to undergo growth arrest differed strikingly. Whereas Type I and II lines had lost both G2/M and G1/S check points, Type III cells retained both. In Type III cells, as in diploid human fibroblasts, mutant p53 expression specifically abrogated G1/S check-point function with no other change in phenotype. These data demonstrate 3 mechanisms for evasion of p53 growth control: (i) direct mutation (ii) indirect inactivation, or (iii) 'avoidance' of activation, most probably due to failure to reach a critical threshold of DNA damage.
Wyllie
F S
FS
Department of Pathology, University of Wales College of Medicine, Cardiff, UK.
Haughton
M F
MF
Blaydes
J P
JP
Schlumberger
M
M
Wynford-Thomas
D
D
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D004249:DNA Damage; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D051381:Rats; D013961:Thyroid Gland / Q000473:pathology*; D013964:Thyroid Neoplasms / Q000473:pathology
D017931:DNA Primers; D001761:Bleomycin