Ueda H, Ullrich S J, Gangemi J D, Kappel C A, Ngo L, Feitelson M A, Jay G
Department of Virology, Jerome H. Holland Laboratory, Rockville, Maryland 20855.
Nat Genet. 1995 Jan;9(1):41-7. doi: 10.1038/ng0195-41.
Structural mutations in the p53 gene are seen in virtually every form of human cancer. To determine whether such mutations are important for initiating tumorigenesis, we have been studying hepatocellular carcinoma, in which most cases are associated with chronic hepatitis B virus infections. Using a transgenic mouse model where expression of a single HBV gene product, the HBx protein, induces progressive changes in the liver, we show that tumour development correlates precisely with p53 binding to HBx in the cytoplasm and complete blockage of p53 entry into the nucleus. Analysis of tumour cell DNA shows no evidence for p53 mutation, except in advanced tumours where a small proportion of cells may have acquired specific base substitutions. Our results suggest that genetic changes in p53 are late events which may contribute to tumour progression.
几乎在每一种人类癌症中都能发现p53基因的结构突变。为了确定这些突变对于启动肿瘤发生是否重要，我们一直在研究肝细胞癌，其中大多数病例与慢性乙型肝炎病毒感染有关。利用一种转基因小鼠模型，其中单一的乙肝病毒基因产物HBx蛋白的表达会在肝脏中引发渐进性变化，我们发现肿瘤发展与p53在细胞质中与HBx的结合以及p53进入细胞核的完全阻断密切相关。对肿瘤细胞DNA的分析没有发现p53突变的证据，除了在晚期肿瘤中，一小部分细胞可能发生了特定的碱基替换。我们的结果表明，p53的基因变化是晚期事件，可能有助于肿瘤进展。
