Stähler F, Roemer K
Department of Virology, University of Saarland Medical School, Homburg/Saar, Germany.
Oncogene. 1998 Dec 31;17(26):3507-12. doi: 10.1038/sj.onc.1202245.
Wild-type (wt) p53 frequently induces apoptosis when expressed in tumor cells whereas mutant p53 acts as an oncoprotein and consequently, stimulates cell proliferation. We report here exceptions to that rule. p53 conformational mutant 175H and DNA contact mutant 273H provoke apoptosis in human p53-deficient Hep3B hepatoma cells with delayed kinetics relative to wt p53. Similarly, c-Myc strongly stimulates apoptosis in these cells. In contrast, viral oncoproteins E1A and E7, and the cellular oncoprotein MDM-2, fail to elicit cytocidal responses. Efficient apoptotic cell death by mutant p53 requires oligomerization as 175H and 273H with deletions between amino acid residues 326 and 347 of the oligomerization domain are nontoxic. Apoptosis by mutant or wt p53 was significantly inhibited by the serine protease inhibitor AEBSF but not by the inactive analog AEBSA. Together, these results suggest that a wt p53-independent control mechanism is operational in Hep3B cells that eliminates cells upon sensing illegitimate proliferation signals originating from certain oncoproteins, including mutant p53 and Myc. We suggest that some tumor cell types lack p53 altogether because they tolerate neither wild-type nor mutant forms of the protein.
野生型（wt）p53在肿瘤细胞中表达时通常会诱导细胞凋亡，而突变型p53则作为一种癌蛋白，从而刺激细胞增殖。我们在此报告该规则的例外情况。p53构象突变体175H和DNA接触突变体273H在人p53缺陷型Hep3B肝癌细胞中引发凋亡，但其动力学相对于wt p53有所延迟。同样，c-Myc在这些细胞中强烈刺激凋亡。相比之下，病毒癌蛋白E1A和E7以及细胞癌蛋白MDM-2未能引发细胞杀伤反应。突变型p53引发有效的凋亡性细胞死亡需要寡聚化，因为在寡聚化结构域氨基酸残基326和347之间有缺失的175H和273H是无毒的。突变型或wt p53诱导的凋亡受到丝氨酸蛋白酶抑制剂AEBSF的显著抑制，但未受到无活性类似物AEBSA的抑制。总之，这些结果表明，一种不依赖wt p53的控制机制在Hep3B细胞中起作用，该机制在感知到源自某些癌蛋白（包括突变型p53和Myc）的非法增殖信号时消除细胞。我们认为，一些肿瘤细胞类型完全缺乏p53，因为它们既不能耐受该蛋白的野生型形式，也不能耐受其突变型形式。
