Bristow R G, Jang A, Peacock J, Chung S, Benchimol S, Hill R P
Department of Radiation Oncology and Research (Division of Experimental Therapeutics, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada.
Oncogene. 1994 Jun;9(6):1527-36.
Recently, it has been suggested that abrogation of the wild type p53 protein function may alter the cellular response to DNA damaging agents, including ionizing radiation. This study was designed to compre the relative radiosensitivity and tumorigenicity of rat embryo fibroblast (REF) cell lines transfected with a mutant form of the p53 gene (plasmid MTp53pro193), alone, or in combination, with the H-ras (plasmid pEJ6.6) and HPV16-E7 (plasmid pJ4 omega 16.E7) oncogenes. Transfection of the mutant p53pro193 gene alone resulted in selected clones having increased radioresistance in culture which correlated with increased mutant p53 expression in these clones. However, the co-transfection of mutant p53 and H-ras genes or triple transfection of mutant p53, H-ras and E7 genes resulted in clones with high mutant p53 expression, significantly increased radioresistance and uniform tumorigenicity. There was no correlation between intrinsic radioresistance and spontaneous metastasis in the tumorigenic REF transfectant clones. Stepwise acquisition of radioresistance and an aggressive tumor cell phenotype is observed when the mutant p53 gene and HPV E7 co-operate with the ras oncogene in transfection assays, and can be correlated to increases in mutant p53 expression.
最近，有人提出野生型p53蛋白功能的缺失可能会改变细胞对包括电离辐射在内的DNA损伤剂的反应。本研究旨在比较单独转染p53基因的突变形式（质粒MTp53pro193），或与H-ras（质粒pEJ6.6）和HPV16-E7（质粒pJ4 omega 16.E7）癌基因联合转染的大鼠胚胎成纤维细胞（REF）细胞系的相对放射敏感性和致瘤性。单独转染突变型p53pro193基因导致所选克隆在培养中具有更高的放射抗性，这与这些克隆中突变型p53表达的增加相关。然而，突变型p53和H-ras基因的共转染或突变型p53、H-ras和E7基因的三联转染导致克隆具有高突变型p53表达、显著增加的放射抗性和一致的致瘤性。在致瘤性REF转染克隆中，内在放射抗性与自发转移之间没有相关性。在转染实验中，当突变型p53基因和HPV E7与ras癌基因协同作用时，观察到放射抗性和侵袭性肿瘤细胞表型的逐步获得，并且这可能与突变型p53表达的增加相关。
