Mammalian cells resistant to tumor suppressor genes
Mammalian cells resistant to tumor suppressor genes
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DOI：
10.1073/pnas.93.16.8390
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发表时间：
1996-08-06
影响因子：
11.1
通讯作者：
Vogelstein, B
中科院分区：
文献类型：
--
作者：
Pietenpol, JA;Lengauer, C;Vogelstein, B
p53 的表达会导致许多正常和肿瘤细胞类型的生长停滞或凋亡，但这两种效应之间的关系仍不清楚。为了开始在基因水平上剖析潜在机制，我们产生了对野生型p53作用具有抵抗力的突变细胞，用ras和温度敏感的p53（tsp53（135val））基因转化的大鼠胚胎成纤维细胞经过化学诱变并选择在p53采用野生型构象的温度（31.5摄氏度）下生长， 选择在 31.5 摄氏度下呈指数生长的克隆。细胞融合实验表明，对 p53 介导的生长停滞产生抗性的突变占主导地位。诱变的克隆不仅能抵抗 p53 介导的生长停滞，还能抵抗 E1A 与 p53 联合诱导的细胞凋亡，并且部分抵抗视网膜母细胞瘤肿瘤抑制因子 pRB。结果表明，单一下游途径控制着生长停滞和细胞凋亡的诱导，并且 p53 和 RB 都通过该途径发挥作用。
Expression of p53 causes growth arrest or apoptosis in many normal and neoplastic cell types, but the relationship between these two effects has remained obscure. To begin to dissect the underlying mechanisms at a genetic level, we have generated mutant cells resistant to the action of wild-type p53, Rat embryo fibroblasts transformed with ras and a temperature-sensitive p53 (tsp53(135val)) gene were chemically mutagenized and selected for growth at a temperature at which p53 adopts a wild-type conformation (31.5 degrees C), Clones that grew exponentially at 31.5 degrees C were selected. Cell fusion experiments demonstrated that the mutations conferring resistance to p53-mediated growth arrest were dominant. The mutagenized clones were resistant not only to p53-mediated growth arrest, but also to the apoptosis induced by E1A in conjunction with p53, and partially resistant to the retino-blastoma tumor suppressor, pRB. The results suggest that a single downstream pathway san control the induction of growth arrest and apoptosis, and that both p53 and RB function through this pathway.