Chk2 phosphorylation of survivin-DeltaEx3 contributes to a DNA damage-sensing checkpoint in cancer.
Chk2 phosphorylation of survivin-DeltaEx3 contributes to a DNA damage-sensing checkpoint in cancer.
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DOI：
10.1158/0008-5472.can-11-4035
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Altieri DC
中科院分区：
文献类型：
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作者：
Lopergolo A;Tavecchio M;Lisanti S;Ghosh JC;Dohi T;Faversani A;Vaira V;Bosari S;Tanigawa N;Delia D;Kossenkov AV;Showe LC;Altieri DC
Survivin是一种癌基因，在癌细胞的细胞保护和有丝分裂中发挥作用。在此我们报道，survivin的一种C末端剪接变体（称为survivin - ΔEx3）在癌细胞中的差异表达与侵袭性疾病和不良预后的标志物密切相关。与其他survivin变体不同，survivin - ΔEx3仅定位于肿瘤细胞的细胞核，并且在DNA损伤期间被检查点激酶Chk2在多个位点磷酸化。Chk2磷酸化位点的突变增强了survivin - ΔEx3在肿瘤细胞中的稳定性，抑制了双链DNA断裂时磷酸化H2AX（γH2AX）的表达，并损害了DNA损伤后的生长。DNA损伤诱导的Chk2磷酸化、p53的稳定、细胞周期蛋白依赖性激酶抑制剂p21的诱导以及同源重组诱导的修复未受影响。在体内，在结直肠腺瘤向癌转变的最早阶段就检测到有活性的Chk2，它在晚期肿瘤中持续存在，并与survivin表达增加相关。总之，我们的研究结果表明，Chk2介导的survivin - ΔEx3磷酸化有助于一种DNA损伤感应检查点，这可能影响癌细胞对基因毒性疗法的敏感性。
Survivin is an oncogene that functions in cancer cell cytoprotection and mitosis. Here we report that differential expression in cancer cells of a C-terminal splice variant of survivin, termed survivin-ΔEx3, is tightly associated with aggressive disease and markers of unfavorable prognosis. In contrast to other survivin variants, survivin-ΔEx3 localized exclusively to nuclei in tumor cells and was phosphorylated at multiple residues by the checkpoint kinase Chk2 during DNA damage. Mutagenesis of the Chk2 phosphorylation sites enhanced the stability of survivin-ΔEx3 in tumor cells, inhibited the expression of phosphorylated H2AX (γH2AX) in response to double strand DNA breaks, and impaired growth after DNA damage. DNA damage-induced Chk2 phosphorylation, stabilization of p53, induction of the cyclin-dependent kinase inhibitor p21, and homologous recombination-induced repair were not affected. In vivo, active Chk2 was detected at the earliest stages of the colorectal adenoma-to-carcinoma transition, persisted in advanced tumors, and correlated with increased survivin expression. Together, our findings suggest that Chk2-mediated phosphorylation of survivin-ΔEx3 contributes to a DNA damage-sensing checkpoint that may affect cancer cell sensitivity to genotoxic therapies.