Sur Surojit, Pagliarini Raymond, Bunz Fred, Rago Carlo, Diaz Luis A, Kinzler Kenneth W, Vogelstein Bert, Papadopoulos Nickolas
The Howard Hughes Medical Institute and The Ludwig Center for Cancer Genetics and Therapeutics, Baltimore, MD 21231, USA.
Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3964-9. doi: 10.1073/pnas.0813333106. Epub 2009 Feb 18.
Through targeted homologous recombination, we developed a panel of matched colorectal cancer cell lines that differ only with respect to their endogenous TP53 status. We then used these lines to define the genes whose expression was altered after DNA damage induced by ionizing radiation. Transcriptome analyses revealed a consistent up-regulation of polo-like kinase 1 (PLK1) as well as other genes controlling the G(2)/M transition in the cells whose TP53 genes were inactivated compared with those with WT TP53 genes. This led to the hypothesis that the viability of stressed cells without WT TP53 depended on PLK1. This hypothesis was validated by demonstrating that stressed cancer cells without WT TP53 alleles were highly sensitive to PLK1 inhibitors, both in vivo and in vitro.
通过靶向同源重组，我们构建了一组匹配的结肠癌细胞系，这些细胞系仅在内源性TP53状态方面存在差异。然后，我们使用这些细胞系来确定在电离辐射诱导的DNA损伤后其表达发生改变的基因。转录组分析显示，与具有野生型TP53基因的细胞相比，TP53基因失活的细胞中polo样激酶1（PLK1）以及其他控制G(2)/M期转换的基因持续上调。这导致了一个假设，即没有野生型TP53的应激细胞的存活依赖于PLK1。通过证明没有野生型TP53等位基因的应激癌细胞在体内和体外对PLK1抑制剂高度敏感，这一假设得到了验证。
