Human thyroid cancer cells as a source of iso-genic, iso-phenotypic cell lines with or without functional p53.
Human thyroid cancer cells as a source of iso-genic, iso-phenotypic cell lines with or without functional p53.
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人甲状腺癌细胞是具有或不具有功能性p53的同类基因，等型细胞系的来源。
DOI：
10.1038/sj.bjc.6690177
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发表时间：
1999-03
影响因子：
8.8
通讯作者：
Wynford-Thomas, D
中科院分区：
文献类型：
--
作者：
Wyllie, FS;Haughton, MF;Rowson, JM;Wynford-Thomas, D
分化型甲状腺癌（与罕见的间变性形式相反）在人类癌症中是不寻常的，表现出非常低的p53突变频率，并且似乎保留了野生型（wt）p53功能，这是通过衍生细胞系对DNA损伤的反应来评估的。使用这样一个细胞系，K1，我们已经测试了实验废除p53功能的效果，通过产生匹配的亚克隆稳定表达neo控制基因，显性阴性突变p53（143 ala）或人乳头瘤病毒蛋白HPV 16 E6。后两组p53功能的丧失通过废除p53依赖性“应激”反应来证实，包括诱导细胞周期蛋白/CDK抑制剂p21 WAF 1和DNA损伤后的G1/S停滞。相比之下，未检测到任何变化的表型的“非应激”克隆，相对于任何以下参数：在单层的增殖率，血清依赖性的增殖或生存，致瘤性，细胞形态，或组织特异性分化标志物。因此，K1系代表相对于p53功能的“中性”背景，允许衍生功能性p53 +或-克隆，其不仅是同基因型的，而且是同表型的。这样的面板应该是一个理想的工具，用它来测试的p53依赖性的细胞应激反应，特别是对潜在的治疗药物的敏感性，从混杂的额外的表型差异，通常伴随着p53功能的丧失。结果还进一步支持了这样的假设，即p53突变本身不足以驱动甲状腺癌进展为侵袭性间变性形式。© 1999癌症研究运动
Differentiated thyroid carcinomas (in contrast to the rarer anaplastic form) are unusual among human cancers in displaying a remarkably low frequency of p53 mutation and appear to retain wild-type (wt) p53 function as assessed by the response of derived cell lines to DNA damage. Using one such cell line, K1, we have tested the effect of experimental abrogation of p53 function by generating matched sub-clones stably expressing either a neo control gene, a dominant-negative mutant p53 (143ala) or human papilloma virus protein HPV16 E6. Loss of p53 function in the latter two groups was confirmed by abolition of p53-dependent ‘stress’ responses including induction of the cyclin/CDK inhibitor p21WAF1 and G1/S arrest following DNA-damage. In contrast, no change was detected in the phenotype of ‘unstressed’ clones, with respect to any of the following parameters: proliferation rate in monolayer, serum-dependence for proliferation or survival, tumorigenicity, cellular morphology, or tissue-specific differentiation markers. The K1 line therefore represents a ‘neutral’ background with respect to p53 function, permitting the derivation of functionally p53 + or − clones which are not only iso-genic but also iso-phenotypic. Such a panel should be an ideal tool with which to test the p53-dependence of cellular stress responses, particularly the sensitivity to potential therapeutic agents, free from the confounding additional phenotypic differences which usually accompany loss of p53 function. The results also further support the hypothesis that p53 mutation alone is not sufficient to drive progression of thyroid cancer to the aggressive anaplastic form. © 1999 Cancer Research Campaign
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