American Association for Cancer Research
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Supplementary Figure 4 from Chk2 Phosphorylation of Survivin-ΔEx3 Contributes to a DNA Damage–Sensing Checkpoint in Cancer

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journal contribution
posted on 2023-03-30, 20:46 authored by Alessia Lopergolo, Michele Tavecchio, Sofia Lisanti, Jagadish C. Ghosh, Takehiko Dohi, Alice Faversani, Valentina Vaira, Silvano Bosari, Nobuhiko Tanigawa, Domenico Delia, Andrew V. Kossenkov, Louise C. Showe, Dario C. Altieri

PDF file - 93K, Multiparametric flow cytometry detection of GammaH2AX reactivity. HCT116 cells were transfected with vector, WT survivin (SVV), survivin-DeltaEx3 or Chk2 phosphorylation-defective survivin-DeltaEx3-Mut3 cDNA, treated with etoposide (A) or camptothecin (B), and analyzed after 16 h for GammaH2AX (y-axis) and PI (x-axis) staining by multiparametric flow cytometry. In panel A, numbers in parenthesis correspond to GammaH2AX fluorescence units after background subtraction.



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. Cancer Res; 72(13); 3251–9. ©2012 AACR.

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