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Chk2 phosphorylation of survivin-DeltaEx3 contributes to a DNA damage-sensing checkpoint in cancer

Lopergolo, Alessia; Tavecchio, Michele LU ; Lisanti, Sofia; Ghosh, Jagadish C; Dohi, Takehiko; Faversani, Alice; Vaira, Valentina; Bosari, Silvano; Tanigawa, Nobuhiko and Delia, Domenico, et al. (2012) In Cancer Research 72(13). p.9-3251
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 double-strand DNA breaks, and impaired growth after DNA damage. DNA damage induced Chk2... (More)

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.

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keywords
Base Sequence, Cell Line, Tumor, Checkpoint Kinase 2, DNA Damage, DNA Primers, Humans, Inhibitor of Apoptosis Proteins, Mutagenesis, Neoplasms, Phosphorylation, Protein-Serine-Threonine Kinases, Reverse Transcriptase Polymerase Chain Reaction, Subcellular Fractions, Journal Article, Research Support, N.I.H., Extramural
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Cancer Research
volume
72
issue
13
pages
9 - 3251
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:84863606096
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-11-4035
language
English
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no
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762fb77c-a717-40dc-aba3-37ddb1d5f0f1
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2017-03-07 09:10:15
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2017-10-01 05:31:38
@article{762fb77c-a717-40dc-aba3-37ddb1d5f0f1,
  abstract     = {<p>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.</p>},
  author       = {Lopergolo, Alessia and Tavecchio, Michele and Lisanti, Sofia and Ghosh, Jagadish C and Dohi, Takehiko and Faversani, Alice and Vaira, Valentina and Bosari, Silvano and Tanigawa, Nobuhiko and Delia, Domenico and Kossenkov, Andrew V and Showe, Louise C and Altieri, Dario C},
  issn         = {1538-7445},
  keyword      = {Base Sequence,Cell Line, Tumor,Checkpoint Kinase 2,DNA Damage,DNA Primers,Humans,Inhibitor of Apoptosis Proteins,Mutagenesis,Neoplasms,Phosphorylation,Protein-Serine-Threonine Kinases,Reverse Transcriptase Polymerase Chain Reaction,Subcellular Fractions,Journal Article,Research Support, N.I.H., Extramural},
  language     = {eng},
  month        = {07},
  number       = {13},
  pages        = {9--3251},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Chk2 phosphorylation of survivin-DeltaEx3 contributes to a DNA damage-sensing checkpoint in cancer},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-11-4035},
  volume       = {72},
  year         = {2012},
}