Resistance to DNA-damaging agents is discordant from experimental metastatic capacity in MEF ras-transformants-expressing gain of function MTp53

被引:18
作者
Bristow, RG
Peacock, J
Jang, A
Kim, J
Hill, RP
Benchimol, S
机构
[1] Univ Toronto, Princess Margaret Hosp, Univ Hlth Network,Ontario Canc Inst, Dept Radiat Oncol, Toronto, ON M5G 2M9, Canada
[2] Univ Toronto, Princess Margaret Hosp, Univ Hlth Network,Ontario Canc Inst, Dept Med Biophys, Toronto, ON M5G 2M9, Canada
关键词
p53; sensitivity; MEF; gain of function; metastasis; transformation;
D O I
10.1038/sj.onc.1206405
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2960 / 2966
页数:7
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