The p38 Mitogen-Activated Protein Kinase Pathway Links the DNA Mismatch Repair System to the G2 Checkpoint and to Resistance to Chemotherapeutic DNA-Methylating Agents

Yuichi Hirose, Makoto Katayama, David Stokoe, Daphne A. Haas-Kogan, Mitchel S. Berger, Russell O. Pieper

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

Although human cells exposed to DNA-methylating agents undergo mismatch repair (MMR)-dependent G2 arrest, the basis for the linkage between MMR and the G2 checkpoint is unclear. We noted that mitogen-activated protein kinase p38α was activated in MMR-proficient human glioma cells exposed to the chemo-therapeutic methylating agent temozolomide (TMZ) but not in paired cells made MMR deficient by expression of a short inhibitory RNA (siRNA) targeted to the MMR protein Mlh1. Furthermore, activation of p38α in MMR-proficient cells was associated with nuclear inactivation of the cell cycle regulator Cdc25C phosphatase and its downstream target Cdc2 and with activation of the G2 checkpoint, actions which were suppressed by the p38α/β inhibitors SB203580 and SB202590 or by expression of a p38α siRNA. Finally, pharmacologic or genetic inhibition of p38α increased the sensitivity of MMR-proficient cells to the cytotoxic actions of TMZ by increasing the percentage of cells that underwent mitotic catastrophe as a consequence of G2 checkpoint bypass. These results suggest that p38α links DNA MMR to the G2 checkpoint and to resistance to chemo-therapeutic DNA-methylating agents. The p38 pathway may therefore represent a new target for the development of agents to sensitize tumor cells to chemotherapeutic methylating agents.

Original languageEnglish
Pages (from-to)8306-8315
Number of pages10
JournalMolecular and Cellular Biology
Volume23
Issue number22
DOIs
Publication statusPublished - 01-11-2003

Fingerprint

DNA Mismatch Repair
p38 Mitogen-Activated Protein Kinases
DNA
temozolomide
cdc25 Phosphatases
RNA
Glioma
Cell Cycle
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Hirose, Yuichi ; Katayama, Makoto ; Stokoe, David ; Haas-Kogan, Daphne A. ; Berger, Mitchel S. ; Pieper, Russell O. / The p38 Mitogen-Activated Protein Kinase Pathway Links the DNA Mismatch Repair System to the G2 Checkpoint and to Resistance to Chemotherapeutic DNA-Methylating Agents. In: Molecular and Cellular Biology. 2003 ; Vol. 23, No. 22. pp. 8306-8315.
@article{d1d34c31731e4cc9b52a0612df10a7f1,
title = "The p38 Mitogen-Activated Protein Kinase Pathway Links the DNA Mismatch Repair System to the G2 Checkpoint and to Resistance to Chemotherapeutic DNA-Methylating Agents",
abstract = "Although human cells exposed to DNA-methylating agents undergo mismatch repair (MMR)-dependent G2 arrest, the basis for the linkage between MMR and the G2 checkpoint is unclear. We noted that mitogen-activated protein kinase p38α was activated in MMR-proficient human glioma cells exposed to the chemo-therapeutic methylating agent temozolomide (TMZ) but not in paired cells made MMR deficient by expression of a short inhibitory RNA (siRNA) targeted to the MMR protein Mlh1. Furthermore, activation of p38α in MMR-proficient cells was associated with nuclear inactivation of the cell cycle regulator Cdc25C phosphatase and its downstream target Cdc2 and with activation of the G2 checkpoint, actions which were suppressed by the p38α/β inhibitors SB203580 and SB202590 or by expression of a p38α siRNA. Finally, pharmacologic or genetic inhibition of p38α increased the sensitivity of MMR-proficient cells to the cytotoxic actions of TMZ by increasing the percentage of cells that underwent mitotic catastrophe as a consequence of G2 checkpoint bypass. These results suggest that p38α links DNA MMR to the G2 checkpoint and to resistance to chemo-therapeutic DNA-methylating agents. The p38 pathway may therefore represent a new target for the development of agents to sensitize tumor cells to chemotherapeutic methylating agents.",
author = "Yuichi Hirose and Makoto Katayama and David Stokoe and Haas-Kogan, {Daphne A.} and Berger, {Mitchel S.} and Pieper, {Russell O.}",
year = "2003",
month = "11",
day = "1",
doi = "10.1128/MCB.23.22.8306-8315.2003",
language = "English",
volume = "23",
pages = "8306--8315",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "22",

}

The p38 Mitogen-Activated Protein Kinase Pathway Links the DNA Mismatch Repair System to the G2 Checkpoint and to Resistance to Chemotherapeutic DNA-Methylating Agents. / Hirose, Yuichi; Katayama, Makoto; Stokoe, David; Haas-Kogan, Daphne A.; Berger, Mitchel S.; Pieper, Russell O.

In: Molecular and Cellular Biology, Vol. 23, No. 22, 01.11.2003, p. 8306-8315.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The p38 Mitogen-Activated Protein Kinase Pathway Links the DNA Mismatch Repair System to the G2 Checkpoint and to Resistance to Chemotherapeutic DNA-Methylating Agents

AU - Hirose, Yuichi

AU - Katayama, Makoto

AU - Stokoe, David

AU - Haas-Kogan, Daphne A.

AU - Berger, Mitchel S.

AU - Pieper, Russell O.

PY - 2003/11/1

Y1 - 2003/11/1

N2 - Although human cells exposed to DNA-methylating agents undergo mismatch repair (MMR)-dependent G2 arrest, the basis for the linkage between MMR and the G2 checkpoint is unclear. We noted that mitogen-activated protein kinase p38α was activated in MMR-proficient human glioma cells exposed to the chemo-therapeutic methylating agent temozolomide (TMZ) but not in paired cells made MMR deficient by expression of a short inhibitory RNA (siRNA) targeted to the MMR protein Mlh1. Furthermore, activation of p38α in MMR-proficient cells was associated with nuclear inactivation of the cell cycle regulator Cdc25C phosphatase and its downstream target Cdc2 and with activation of the G2 checkpoint, actions which were suppressed by the p38α/β inhibitors SB203580 and SB202590 or by expression of a p38α siRNA. Finally, pharmacologic or genetic inhibition of p38α increased the sensitivity of MMR-proficient cells to the cytotoxic actions of TMZ by increasing the percentage of cells that underwent mitotic catastrophe as a consequence of G2 checkpoint bypass. These results suggest that p38α links DNA MMR to the G2 checkpoint and to resistance to chemo-therapeutic DNA-methylating agents. The p38 pathway may therefore represent a new target for the development of agents to sensitize tumor cells to chemotherapeutic methylating agents.

AB - Although human cells exposed to DNA-methylating agents undergo mismatch repair (MMR)-dependent G2 arrest, the basis for the linkage between MMR and the G2 checkpoint is unclear. We noted that mitogen-activated protein kinase p38α was activated in MMR-proficient human glioma cells exposed to the chemo-therapeutic methylating agent temozolomide (TMZ) but not in paired cells made MMR deficient by expression of a short inhibitory RNA (siRNA) targeted to the MMR protein Mlh1. Furthermore, activation of p38α in MMR-proficient cells was associated with nuclear inactivation of the cell cycle regulator Cdc25C phosphatase and its downstream target Cdc2 and with activation of the G2 checkpoint, actions which were suppressed by the p38α/β inhibitors SB203580 and SB202590 or by expression of a p38α siRNA. Finally, pharmacologic or genetic inhibition of p38α increased the sensitivity of MMR-proficient cells to the cytotoxic actions of TMZ by increasing the percentage of cells that underwent mitotic catastrophe as a consequence of G2 checkpoint bypass. These results suggest that p38α links DNA MMR to the G2 checkpoint and to resistance to chemo-therapeutic DNA-methylating agents. The p38 pathway may therefore represent a new target for the development of agents to sensitize tumor cells to chemotherapeutic methylating agents.

UR - http://www.scopus.com/inward/record.url?scp=0242663968&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0242663968&partnerID=8YFLogxK

U2 - 10.1128/MCB.23.22.8306-8315.2003

DO - 10.1128/MCB.23.22.8306-8315.2003

M3 - Article

VL - 23

SP - 8306

EP - 8315

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 22

ER -