Chk2 phosphorylation of survivin-ΔEx3 contributes to a DNA damage-sensing checkpoint in cancer

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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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 doublestrand 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 adenomato- 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.

Original languageEnglish (US)
Pages (from-to)3251-3259
Number of pages9
JournalCancer Research
Volume72
Issue number13
DOIs
StatePublished - Jul 1 2012

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Chk2 phosphorylation of survivin-ΔEx3 contributes to a DNA damage-sensing checkpoint in cancer'. Together they form a unique fingerprint.

Cite this