Resistance to DNA-damaging agents is discordant from experimental metastatic capacity in MEF ras-transformants-expressing gain of function MTp53
Resistance to DNA-damaging agents is discordant from experimental metastatic capacity in MEF ras-transformants-expressing gain of function MTp53
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DOI：
10.1038/sj.onc.1206405
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发表时间：
2003-05-15
期刊：
影响因子：
8
通讯作者：
Benchimol, S
中科院分区：
文献类型：
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作者：
Bristow, RG;Peacock, J;Benchimol, S
野生型 p53 (WTp53) 蛋白表达丧失或选定突变 p53 (MTp53) 蛋白功能获得后，肿瘤细胞可以获得继发的侵袭性表型。然而，尚不清楚攻击性表型的发展是否相互关联。在此，我们报告了可变表达 MTp53 蛋白的同基因 p53(-/-) MEF ras 转化子的放射敏感性、化学敏感性和体内生长特征。初步实验揭示了预先存在的 p53(-/-) MEF 细胞群的亚克隆内细胞对 DNA 损伤剂（即电离辐射、紫外线辐射、顺铂和甲氨蝶呤）的敏感性存在显着的克隆异质性。此外，在用激活的ras等位基因转化的p53(-/-) MEF细胞的硅克隆中也观察到了这种差异敏感性，这表明次级遗传事件和克隆选择，而不是细胞转化本身，可能驱动某些无效p53肿瘤的耐药模式。相反，将 MTp53 等位基因 (MTp53pro193) 额外转染至 p53(-/-) MEF 转化体和 p53(-/-) DP-16 Friend 红白血病细胞后，观察到一致的耐药性，这与该等位基因 MTp53 功能的增强一致。 MTp53pro193 表达并未增强相对肿瘤生长速率和实验转移能力。我们的结果支持这样的概念：MTp53pro193 功能的获得导致显性克隆的选择，这些克隆可能在癌症治疗后表现出细胞耐药性。
Tumor cells can acquire aggressive phenotypes secondary to the loss of expression of the wild-type p53 (WTp53) protein or by the gain of function for selected mutant p53 (MTp53) proteins. However, it is unclear as to whether the development of aggressive phenotypes is inter-related. Herein we report the radiosensitivity, chemosensitivity, and in vivo growth characteristics of isogenic p53(-/-) MEF ras-transformants that variably express an MTp53 protein. Initial experiments revealed significant clonal heterogeneity with respect to cellular sensitivity to DNA-damaging agents (i.e. ionizing radiation, ultraviolet radiation, cis-platinum, and methotrexate) within subclones of a pre-existing p53(-/-) MEF cell population. Moreover, this differential sensitivity was also observed within suliclones of p53(-/-) MEF cells transformed with an activated ras allele, suggesting that secondary genetic events and clonal selection, but not cellular transformation per se, may drive the resistance patterns for certain null-p53 tumors. In contrast, uniform resistance was observed following the additional transfection of an MTp53 allele (MTp53pro193) into p53(-/-) MEF transformants and p53(-/-) DP-16 Friend erythroleukemia cells, consistent with a gain of MTp53 function for this allele. Relative tumor growth rate and experimental metastatic ability was not enhanced by MTp53pro193 expression. Our results support the concept that gain of MTp53pro193 function leads to the selection of dominant clones, which may exhibit cellular resistance following cancer therapy.