Ossovskaya V S, Mazo I A, Chernov M V, Chernova O B, Strezoska Z, Kondratov R, Stark G R, Chumakov P M, Gudkov A V
Department of Genetics, University of Illinois, Chicago, IL 60607, USA.
Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10309-14. doi: 10.1073/pnas.93.19.10309.
p53 is a multifunctional tumor suppressor protein involved in the negative control of cell growth. Mutations in p53 cause alterations in cellular phenotype, including immortalization, neoplastic transformation, and resistance to DNA-damaging drugs. To help dissect distinct functions of p53, a set of genetic suppressor elements (GSEs) capable of inducing different p53-related phenotypes in rodent embryo fibroblasts was isolated from a retroviral library of random rat p53 cDNA fragments. All the GSEs were 100-300 nucleotides long and were in the sense orientation. They fell into four classes, corresponding to the transactivator (class I), DNA-binding (class II), and C-terminal (class III) domains of the protein and the 3'-untranslated region of the mRNA (class IV). GSEs in all four classes promoted immortalization of primary cells, but only members of classes I and III cooperated with activated ras to transform cells, and only members of class III conferred resistance to etoposide and strongly inhibited transcriptional transactivation by p53. These observations suggest that processes related to control of senescence, response to DNA damage, and transformation involve different functions of the p53 protein and furthermore indicate a regulatory role for the 3'-untranslated region of p53 mRNA.
p53是一种多功能肿瘤抑制蛋白，参与细胞生长的负调控。p53突变会导致细胞表型改变，包括永生化、肿瘤转化以及对DNA损伤药物的抗性。为了帮助剖析p53的不同功能，从随机大鼠p53 cDNA片段的逆转录病毒文库中分离出一组能够在啮齿动物胚胎成纤维细胞中诱导不同p53相关表型的遗传抑制元件（GSE）。所有GSE长度为100 - 300个核苷酸，且为正义方向。它们分为四类，分别对应于该蛋白的反式激活因子（I类）、DNA结合（II类）和C末端（III类）结构域以及mRNA的3'非翻译区（IV类）。所有四类中的GSE都能促进原代细胞永生化，但只有I类和III类的成员能与激活的ras协同作用使细胞转化，并且只有III类的成员赋予对依托泊苷的抗性并强烈抑制p53的转录反式激活。这些观察结果表明，与衰老控制、对DNA损伤的反应以及转化相关的过程涉及p53蛋白的不同功能，此外还表明p53 mRNA的3'非翻译区具有调控作用。
