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 journalArticle

12 Citations (Scopus)

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

Fingerprint

DNA Damage
Phosphorylation
Neoplasms
Cyclin-Dependent Kinase Inhibitor p21
Recombinational DNA Repair
DNA Breaks
Cytoprotection
Oncogenes
Mitosis
Mutagenesis
Colorectal Neoplasms
Phosphotransferases
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lopergolo, A., Tavecchio, M., Lisanti, S., Ghosh, J. C., Dohi, T., Faversani, A., ... Altieri, D. C. (2012). Chk2 phosphorylation of survivin-ΔEx3 contributes to a DNA damage-sensing checkpoint in cancer. Cancer Research, 72(13), 3251-3259. https://doi.org/10.1158/0008-5472.CAN-11-4035
Lopergolo, Alessia ; Tavecchio, Michele ; Lisanti, Sofia ; Ghosh, Jagadish C. ; Dohi, Takehiko ; Faversani, Alice ; Vaira, Valentina ; Bosari, Silvano ; Tanigawa, Nobuhiko ; Delia, Domenico ; Kossenkov, Andrew V. ; Showe, Louise C. ; Altieri, Dario C. / Chk2 phosphorylation of survivin-ΔEx3 contributes to a DNA damage-sensing checkpoint in cancer. In: Cancer Research. 2012 ; Vol. 72, No. 13. pp. 3251-3259.
@article{326abcd07db5409fb8466d4c8ce064a2,
title = "Chk2 phosphorylation of survivin-ΔEx3 contributes to a DNA damage-sensing checkpoint in cancer",
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.",
author = "Alessia Lopergolo and Michele Tavecchio and Sofia Lisanti and Ghosh, {Jagadish C.} and Takehiko Dohi and Alice Faversani and Valentina Vaira and Silvano Bosari and Nobuhiko Tanigawa and Domenico Delia and Kossenkov, {Andrew V.} and Showe, {Louise C.} and Altieri, {Dario C.}",
year = "2012",
month = "7",
day = "1",
doi = "10.1158/0008-5472.CAN-11-4035",
language = "English (US)",
volume = "72",
pages = "3251--3259",
journal = "Cancer Research",
issn = "0008-5472",
number = "13",

}

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 2012, 'Chk2 phosphorylation of survivin-ΔEx3 contributes to a DNA damage-sensing checkpoint in cancer', Cancer Research, vol. 72, no. 13, pp. 3251-3259. https://doi.org/10.1158/0008-5472.CAN-11-4035

Chk2 phosphorylation of survivin-ΔEx3 contributes to a DNA damage-sensing checkpoint in cancer. / Lopergolo, Alessia; Tavecchio, Michele; Lisanti, Sofia; Ghosh, Jagadish C.; Dohi, Takehiko; Faversani, Alice; Vaira, Valentina; Bosari, Silvano; Tanigawa, Nobuhiko; Delia, Domenico; Kossenkov, Andrew V.; Showe, Louise C.; Altieri, Dario C.

In: Cancer Research, Vol. 72, No. 13, 01.07.2012, p. 3251-3259.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Chk2 phosphorylation of survivin-ΔEx3 contributes to a DNA damage-sensing checkpoint in cancer

AU - Lopergolo, Alessia

AU - Tavecchio, Michele

AU - Lisanti, Sofia

AU - Ghosh, Jagadish C.

AU - Dohi, Takehiko

AU - Faversani, Alice

AU - Vaira, Valentina

AU - Bosari, Silvano

AU - Tanigawa, Nobuhiko

AU - Delia, Domenico

AU - Kossenkov, Andrew V.

AU - Showe, Louise C.

AU - Altieri, Dario C.

PY - 2012/7/1

Y1 - 2012/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84863606096&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863606096&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-11-4035

DO - 10.1158/0008-5472.CAN-11-4035

M3 - Article

C2 - 22586065

AN - SCOPUS:84863606096

VL - 72

SP - 3251

EP - 3259

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 13

ER -