Lin J, Teresky A K, Levine A J
Department of Molecular Biology, Princeton University, New Jersey 08544-1014, USA.
Oncogene. 1995 Jun 15;10(12):2387-90.
Some mutant forms of the p53 protein have been shown to gain new functions that are not shared by the wild-type p53 protein; (1) mutant p53 proteins can transcriptionally transactivate the multi-drug resistance gene-1 (MDR-1) and (2) when expressed in non-tumorigenic cells with no endogenous p53 protein, mutant p53 proteins can enhance the tumorigenic potential of these cells (Dittmer et al., 1993). It has recently been shown (Lin et al., 1994b) that the transcriptional activator domain of the p53 protein contains two amino acids, leu-22 and trp-23, which are required by the wild-type p53 protein for transcriptional activity. To determine whether these same amino acid residues are utilized by mutant p53 proteins for their gain of function phenotype, the triple mutant p53 protein (at residues 22 and 23 in the transactivation domain and residue 281 in the DNA binding domain--a gain of function mutant) was made. While the p53-281 mutant transcriptionally activates the MDR-1 gene and enhances the tumorigenic potential of cells it is expressed in, the 22, 23, 281 triple mutant failed to carry out either of these functions.
一些p53蛋白的突变形式已被证明获得了野生型p53蛋白所没有的新功能；（1）突变型p53蛋白可转录激活多药耐药基因-1（MDR-1），并且（2）当在没有内源性p53蛋白的非致瘤细胞中表达时，突变型p53蛋白可增强这些细胞的致瘤潜力（迪特默等人，1993年）。最近有研究表明（林等人，1994b），p53蛋白的转录激活结构域包含两个氨基酸，亮氨酸-22和色氨酸-23，野生型p53蛋白的转录活性需要这两个氨基酸。为了确定突变型p53蛋白是否利用这些相同的氨基酸残基来实现其功能获得表型，构建了三突变p53蛋白（在转录激活结构域的第22和23位残基以及DNA结合结构域的第281位残基——一种功能获得突变体）。虽然p53-281突变体可转录激活MDR-1基因并增强其表达细胞的致瘤潜力，但22、23、281三突变体无法执行这两种功能中的任何一种。
