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

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Chk2 phosphorylation of survivin-DeltaEx3 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.

I: Cancer Research, Vol. 72, Nr. 13, 01.07.2012, s. 3251-9.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

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-DeltaEx3 contributes to a DNA damage-sensing checkpoint in cancer', Cancer Research, vol. 72, nr. 13, s. 3251-9. https://doi.org/10.1158/0008-5472.CAN-11-4035

APA

Lopergolo, A., Tavecchio, M., Lisanti, S., Ghosh, J. C., Dohi, T., Faversani, A., ... Altieri, D. C. (2012). Chk2 phosphorylation of survivin-DeltaEx3 contributes to a DNA damage-sensing checkpoint in cancer. Cancer Research, 72(13), 3251-9. https://doi.org/10.1158/0008-5472.CAN-11-4035

CBE

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-DeltaEx3 contributes to a DNA damage-sensing checkpoint in cancer. Cancer Research. 72(13):3251-9. https://doi.org/10.1158/0008-5472.CAN-11-4035

MLA

Vancouver

Author

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-DeltaEx3 contributes to a DNA damage-sensing checkpoint in cancer. I: Cancer Research. 2012 ; Vol. 72, Nr. 13. s. 3251-9.

RIS

TY - JOUR

T1 - Chk2 phosphorylation of survivin-DeltaEx3 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

N1 - ©2012 AACR.

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 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.

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 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.

KW - Base Sequence

KW - Cell Line, Tumor

KW - Checkpoint Kinase 2

KW - DNA Damage

KW - DNA Primers

KW - Humans

KW - Inhibitor of Apoptosis Proteins

KW - Mutagenesis

KW - Neoplasms

KW - Phosphorylation

KW - Protein-Serine-Threonine Kinases

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Subcellular Fractions

KW - Journal Article

KW - Research Support, N.I.H., Extramural

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

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

M3 - Article

VL - 72

SP - 3251

EP - 3259

JO - Cancer research. Supplement

T2 - Cancer research. Supplement

JF - Cancer research. Supplement

SN - 1538-7445

IS - 13

ER -