Whitesell L, Sutphin P, An W G, Schulte T, Blagosklonny M V, Neckers L
Department of Pediatrics, Steele Memorial Children's Research Center, University of Arizona, Tucson 85724, USA.
Oncogene. 1997 Jun 12;14(23):2809-16. doi: 10.1038/sj.onc.1201120.
Mutation of the tumor suppressor gene p53 is the most common genetic abnormality detected in human cancers. Wild type p53 is a short-lived protein with very low basal intracellular levels. Most mutated forms of the protein, however, display markedly increased intracellular levels as an essential feature of their positive transforming activity. In this report, we have used selective inhibitors of the 20S proteasome to demonstrate that processing of p53 by ubiquitination and proteasome-mediated degradation is impaired by commonly occuring mutations of the protein. We found that this impairment of p53 turnover can be reversed by treatment of tumor cells with the benzoquinone ansamycin, geldanamycin, leading to a marked reduction in intracellular p53 levels. Finally, using cells which over-express a mutant p53 protein, we were able to demonstrate that restoration of proteasome-mediated degradation by geldanamycin is accompanied by p53 polyubiquitination. Although much remains to be learned about the mechanisms involved, our data demonstrate that selective de-stabilization of mutant transforming proteins such as p53 can be achieved pharmacologically with agents such as geldanamycin which modify the function of molecular chaperone proteins within tumor cells.
肿瘤抑制基因p53的突变是在人类癌症中检测到的最常见的基因异常。野生型p53是一种半衰期短的蛋白质，细胞内基础水平极低。然而，该蛋白的大多数突变形式表现出细胞内水平显著增加，这是其正向转化活性的一个基本特征。在本报告中，我们使用了20S蛋白酶体的选择性抑制剂来证明，p53通过泛素化和蛋白酶体介导的降解过程会因该蛋白常见的突变而受损。我们发现，用苯醌安莎霉素、格尔德霉素处理肿瘤细胞可以逆转p53周转的这种损伤，导致细胞内p53水平显著降低。最后，使用过表达突变型p53蛋白的细胞，我们能够证明格尔德霉素恢复蛋白酶体介导的降解伴随着p53多聚泛素化。尽管关于其中涉及的机制仍有许多有待了解，但我们的数据表明，使用格尔德霉素等药物可以在药理学上实现对突变型转化蛋白（如p53）的选择性去稳定化，这些药物可改变肿瘤细胞内分子伴侣蛋白的功能。
