Zuzarte P C, Farrance I K, Simpson P C, Wildeman A G
Department of Molecular Biology and Genetics, University of Guelph, Ontario, Canada.
Biochim Biophys Acta. 2000 Dec 15;1517(1):82-90. doi: 10.1016/s0167-4781(00)00261-x.
The large tumor antigen (TAg) of simian virus 40 is able to transform cells through interactions with cellular proteins, notably p53 and Rb. Among the other proteins that form complexes with TAg is TEF-1, a transcription factor utilized by the viral enhancer to activate expression of the early gene which encodes TAg. We show that fibroblasts contain several alternately spliced TEF-1 mRNAs, the most abundant of which encodes a protein with an additional four amino acid exon compared to the database entry for Hela cell TEF-1. Transformation by TAg induces alternate splicing, producing a more abundant form lacking this exon and matching the published sequence. Splicing variants lacking this exon were detected in mouse pancreatic tumors and in cell lines derived from human pancreatic cancers, in contrast to a single isoform with the exon in normal mouse pancreas. A total of eight splice variants were identified, with the loss of the four amino acid exon typical of transformed cells. These and other data presented suggest that TAg 're-models' host cell transcription factors that are used early in viral infection, and thereby mimics an event that naturally occurs during transformation. The data indicate that TEF-1 alterations may be a hallmark feature of tumorigenesis.
猴病毒40的大肿瘤抗原（TAg）能够通过与细胞蛋白（尤其是p53和Rb）相互作用来转化细胞。与TAg形成复合物的其他蛋白中包括TEF-1，它是一种转录因子，病毒增强子利用它来激活编码TAg的早期基因的表达。我们发现成纤维细胞含有几种可变剪接的TEF-1 mRNA，其中最丰富的一种编码的蛋白与海拉细胞TEF-1的数据库条目相比，多了一个包含四个氨基酸的外显子。TAg介导的转化会诱导可变剪接，产生一种更丰富的缺乏该外显子的形式，与已发表的序列相符。在小鼠胰腺肿瘤和源自人类胰腺癌的细胞系中检测到了缺乏该外显子的剪接变体，而正常小鼠胰腺中只有一种带有该外显子的异构体。总共鉴定出了八种剪接变体，转化细胞中典型的缺失四个氨基酸外显子的情况很常见。本文呈现的这些及其他数据表明，TAg“重塑”了病毒感染早期所利用的宿主细胞转录因子，从而模拟了转化过程中自然发生的一个事件。这些数据表明，TEF-1的改变可能是肿瘤发生的一个标志性特征。
