Wyllie F S, Haughton M F, Blaydes J P, Schlumberger M, Wynford-Thomas D
Department of Pathology, University of Wales College of Medicine, Cardiff, UK.
Oncogene. 1995 Jan 5;10(1):49-59.
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.
以甲状腺作为多步骤上皮肿瘤发生的模型，我们使用了具有代表性的细胞系，将恶性转化程度与p53的功能状态以及细胞周期检查点的完整性联系起来。观察到三种不同的表型：I型细胞系来源于低分化的人类甲状腺癌，表达高水平的突变型p53蛋白；II型同样为低分化，但来源于大鼠，显示野生型（wt）p53过表达且细胞间存在显著异质性；III型来源于高分化的人类癌症，wt p53水平均一且较低。所有含有wt p53的细胞系在DNA损伤时p53的诱导均接近正常。然而，经历生长停滞的能力却有显著差异。I型和II型细胞系失去了G2/M和G1/S检查点，而III型细胞系两者均保留。在III型细胞中，如同在二倍体人类成纤维细胞中一样，突变型p53的表达特异性地废除了G1/S检查点功能，而表型没有其他变化。这些数据证明了逃避p53生长控制的三种机制：（i）直接突变；（ii）间接失活；或（iii）“避免”激活，很可能是由于未能达到DNA损伤的临界阈值。
