Role of a DNA damage checkpoint pathway in ionizing radiation-induced glioblastoma cell migration and invasion

Issai Vanan, Zhiwan Dong, Elena Tosti, Gregg Warshaw, Marc Symons, Rosamaria Ruggieri

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Ionizing radiation (IR) induces a DNA damage response that includes activation of cell cycle checkpoints, leading to cell cycle arrest. In addition, IR enhances cell invasiveness of glioblastoma cells, among other tumor cell types. Using RNA interference, we found that the protein kinase MRK, previously implicated in the DNA damage response to IR, also inhibits IR-induced cell migration and invasion of glioblastoma cells. We showed that MRK activation by IR requires the checkpoint protein Nbs1 and that Nbs1 is also required for IR-stimulated migration. In addition, we show that MRK acts upstream of Chk2 and that Chk2 is also required for IR-stimulated migration and invasion. Thus, we have identified Nbs1, MRK, and Chk2 as elements of a novel signaling pathway that mediates IR-stimulated cell migration and invasion. Interestingly, we found that inhibition of cell cycle progression, either with the CDK1/2 inhibitor CGP74514A or by downregulation of the CDC25A protein phosphatase, restores IR-induced migration and invasion in cells depleted of MRK or Chk2. These data indicate that cell cycle progression, at least in the context of IR, exerts a negative control on the invasive properties of glioblastoma cells and that checkpoint proteins mediate IRinduced invasive behavior by controlling cell cycle arrest.

Original languageEnglish (US)
Pages (from-to)1199-1208
Number of pages10
JournalCellular and Molecular Neurobiology
Volume32
Issue number7
DOIs
StatePublished - Oct 1 2012

Fingerprint

Glioblastoma
Ionizing Radiation
DNA Damage
Cell Movement
Cell Cycle Checkpoints
Cell Cycle
Phosphoprotein Phosphatases
RNA Interference
Protein Kinases
Proteins
Down-Regulation

Keywords

  • Cell cycle arrest
  • Checkpoint
  • Glioblastoma
  • Invasion
  • Migration

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

Role of a DNA damage checkpoint pathway in ionizing radiation-induced glioblastoma cell migration and invasion. / Vanan, Issai; Dong, Zhiwan; Tosti, Elena; Warshaw, Gregg; Symons, Marc; Ruggieri, Rosamaria.

In: Cellular and Molecular Neurobiology, Vol. 32, No. 7, 01.10.2012, p. 1199-1208.

Research output: Contribution to journalArticle

Vanan, Issai ; Dong, Zhiwan ; Tosti, Elena ; Warshaw, Gregg ; Symons, Marc ; Ruggieri, Rosamaria. / Role of a DNA damage checkpoint pathway in ionizing radiation-induced glioblastoma cell migration and invasion. In: Cellular and Molecular Neurobiology. 2012 ; Vol. 32, No. 7. pp. 1199-1208.
@article{c8708607464848c8bb4dde79cd420ed4,
title = "Role of a DNA damage checkpoint pathway in ionizing radiation-induced glioblastoma cell migration and invasion",
abstract = "Ionizing radiation (IR) induces a DNA damage response that includes activation of cell cycle checkpoints, leading to cell cycle arrest. In addition, IR enhances cell invasiveness of glioblastoma cells, among other tumor cell types. Using RNA interference, we found that the protein kinase MRK, previously implicated in the DNA damage response to IR, also inhibits IR-induced cell migration and invasion of glioblastoma cells. We showed that MRK activation by IR requires the checkpoint protein Nbs1 and that Nbs1 is also required for IR-stimulated migration. In addition, we show that MRK acts upstream of Chk2 and that Chk2 is also required for IR-stimulated migration and invasion. Thus, we have identified Nbs1, MRK, and Chk2 as elements of a novel signaling pathway that mediates IR-stimulated cell migration and invasion. Interestingly, we found that inhibition of cell cycle progression, either with the CDK1/2 inhibitor CGP74514A or by downregulation of the CDC25A protein phosphatase, restores IR-induced migration and invasion in cells depleted of MRK or Chk2. These data indicate that cell cycle progression, at least in the context of IR, exerts a negative control on the invasive properties of glioblastoma cells and that checkpoint proteins mediate IRinduced invasive behavior by controlling cell cycle arrest.",
keywords = "Cell cycle arrest, Checkpoint, Glioblastoma, Invasion, Migration",
author = "Issai Vanan and Zhiwan Dong and Elena Tosti and Gregg Warshaw and Marc Symons and Rosamaria Ruggieri",
year = "2012",
month = "10",
day = "1",
doi = "10.1007/s10571-012-9846-y",
language = "English (US)",
volume = "32",
pages = "1199--1208",
journal = "Cellular and Molecular Neurobiology",
issn = "0272-4340",
publisher = "Springer New York",
number = "7",

}

TY - JOUR

T1 - Role of a DNA damage checkpoint pathway in ionizing radiation-induced glioblastoma cell migration and invasion

AU - Vanan, Issai

AU - Dong, Zhiwan

AU - Tosti, Elena

AU - Warshaw, Gregg

AU - Symons, Marc

AU - Ruggieri, Rosamaria

PY - 2012/10/1

Y1 - 2012/10/1

N2 - Ionizing radiation (IR) induces a DNA damage response that includes activation of cell cycle checkpoints, leading to cell cycle arrest. In addition, IR enhances cell invasiveness of glioblastoma cells, among other tumor cell types. Using RNA interference, we found that the protein kinase MRK, previously implicated in the DNA damage response to IR, also inhibits IR-induced cell migration and invasion of glioblastoma cells. We showed that MRK activation by IR requires the checkpoint protein Nbs1 and that Nbs1 is also required for IR-stimulated migration. In addition, we show that MRK acts upstream of Chk2 and that Chk2 is also required for IR-stimulated migration and invasion. Thus, we have identified Nbs1, MRK, and Chk2 as elements of a novel signaling pathway that mediates IR-stimulated cell migration and invasion. Interestingly, we found that inhibition of cell cycle progression, either with the CDK1/2 inhibitor CGP74514A or by downregulation of the CDC25A protein phosphatase, restores IR-induced migration and invasion in cells depleted of MRK or Chk2. These data indicate that cell cycle progression, at least in the context of IR, exerts a negative control on the invasive properties of glioblastoma cells and that checkpoint proteins mediate IRinduced invasive behavior by controlling cell cycle arrest.

AB - Ionizing radiation (IR) induces a DNA damage response that includes activation of cell cycle checkpoints, leading to cell cycle arrest. In addition, IR enhances cell invasiveness of glioblastoma cells, among other tumor cell types. Using RNA interference, we found that the protein kinase MRK, previously implicated in the DNA damage response to IR, also inhibits IR-induced cell migration and invasion of glioblastoma cells. We showed that MRK activation by IR requires the checkpoint protein Nbs1 and that Nbs1 is also required for IR-stimulated migration. In addition, we show that MRK acts upstream of Chk2 and that Chk2 is also required for IR-stimulated migration and invasion. Thus, we have identified Nbs1, MRK, and Chk2 as elements of a novel signaling pathway that mediates IR-stimulated cell migration and invasion. Interestingly, we found that inhibition of cell cycle progression, either with the CDK1/2 inhibitor CGP74514A or by downregulation of the CDC25A protein phosphatase, restores IR-induced migration and invasion in cells depleted of MRK or Chk2. These data indicate that cell cycle progression, at least in the context of IR, exerts a negative control on the invasive properties of glioblastoma cells and that checkpoint proteins mediate IRinduced invasive behavior by controlling cell cycle arrest.

KW - Cell cycle arrest

KW - Checkpoint

KW - Glioblastoma

KW - Invasion

KW - Migration

UR - http://www.scopus.com/inward/record.url?scp=84867581593&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867581593&partnerID=8YFLogxK

U2 - 10.1007/s10571-012-9846-y

DO - 10.1007/s10571-012-9846-y

M3 - Article

C2 - 22552889

AN - SCOPUS:84867581593

VL - 32

SP - 1199

EP - 1208

JO - Cellular and Molecular Neurobiology

JF - Cellular and Molecular Neurobiology

SN - 0272-4340

IS - 7

ER -