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

研究成果: Article査読

121 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)8306-8315
ページ数10
ジャーナルMolecular and Cellular Biology
23
22
DOI
出版ステータスPublished - 11-2003
外部発表はい

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 細胞生物学

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