Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Ramat Aviv, Tel-Aviv, Israel.
J Immunother. 2010 Feb-Mar;33(2):146-54. doi: 10.1097/CJI.0b013e3181be14dc.
The tumor suppressor gene p53 is mutated in more than half of human tumors. One important characteristic of p53 mutants is their accumulation in the nucleus of cancer cells. Thus, reactivation of mutant p53 proteins may trigger massive apoptosis in tumor cells. Pharmacologic methods are currently under development to induce mutant p53 proteins to resume their wild-type function. We have identified a human single-chain Fv fragment, designated as transcriptional transactivation and apoptosis restoring (TAR1), which specifically and with high affinity binds to mutant p53 and restores its wild-type active conformation. Binding of TAR1 to mutant p53 induced transcriptional transactivation of p53 target genes and down-regulation of mutant p53 transcriptional target genes. TAR1 treatment induced apoptosis in a variety of cell lines endogenously expressing p53 carrying different point mutations DNA contact or structural p53 mutants. Moreover, in an animal model of mice carrying human xenografts, TAR1 induced tumor regression with no apparent deleterious side effects. Thus, it may be considered as a potential candidate for anticancer treatment, targeting tumors with mutant p53.
抑癌基因 p53 在超过一半的人类肿瘤中发生突变。p53 突变体的一个重要特征是其在癌细胞核内的积累。因此，重新激活突变型 p53 蛋白可能会引发肿瘤细胞的大量凋亡。目前正在开发药理学方法来诱导突变型 p53 蛋白恢复其野生型功能。我们已经鉴定出一种人源单链 Fv 片段，命名为转录激活和凋亡恢复（TAR1），它特异性地以高亲和力结合突变型 p53 并恢复其野生型的活性构象。TAR1 与突变型 p53 的结合诱导了 p53 靶基因的转录激活，并下调了突变型 p53 的转录靶基因。TAR1 处理诱导了多种内源性表达携带不同点突变的 p53 的细胞系发生凋亡，这些点突变影响了 p53 的 DNA 结合或结构。此外，在携带人源异种移植物的小鼠动物模型中，TAR1 诱导肿瘤消退，没有明显的有害副作用。因此，它可以被认为是一种针对携带突变型 p53 的肿瘤的潜在抗癌治疗候选药物。
