This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hirose, Y.
Right arrow Articles by Pieper, R. O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hirose, Y.
Right arrow Articles by Pieper, R. O.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, November 2003, p. 8306-8315, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8306-8315.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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,{dagger} Makoto Katayama, David Stokoe, Daphne A. Haas-Kogan, Mitchel S. Berger, and Russell O. Pieper*

UCSF Cancer Center, Department of Neurological Surgery, and The Brain Tumor Research Center, University of California—San Francisco, San Francisco, California 94115-0875

Received 7 April 2003/ Returned for modification 20 May 2003/ Accepted 12 August 2003

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 p38{alpha} was activated in MMR-proficient human glioma cells exposed to the chemotherapeutic 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 p38{alpha} 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 p38{alpha}/ß inhibitors SB203580 and SB202590 or by expression of a p38{alpha} siRNA. Finally, pharmacologic or genetic inhibition of p38{alpha} 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 p38{alpha} links DNA MMR to the G2 checkpoint and to resistance to chemotherapeutic 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.

* Corresponding author. Mailing address: UCSF Cancer Center, 2340 Sutter St., San Francisco, CA 94115-0875. Phone: (415) 502-7132. Fax: (415) 502-6779. E-mail: rpieper{at}cc.ucsf.edu.

{dagger} Present address: Department of Neurosurgery, Keio University School of Medicine, Tokyo 160-8582, Japan.

Molecular and Cellular Biology, November 2003, p. 8306-8315, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8306-8315.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Topping, R. P., Wilkinson, J. C., Scarpinato, K. D. (2009). Mismatch Repair Protein Deficiency Compromises Cisplatin-induced Apoptotic Signaling. J. Biol. Chem. 284: 14029-14039 [Abstract] [Full Text]  
  • Wagner, M. W., Li, L. S., Morales, J. C., Galindo, C. L., Garner, H. R., Bornmann, W. G., Boothman, D. A. (2008). Role of c-Abl Kinase in DNA Mismatch Repair-dependent G2 Cell Cycle Checkpoint Arrest Responses. J. Biol. Chem. 283: 21382-21393 [Abstract] [Full Text]  
  • Li, L. S., Morales, J. C., Hwang, A., Wagner, M. W., Boothman, D. A. (2008). DNA Mismatch Repair-dependent Activation of c-Abl/p73{alpha}/GADD45{alpha}-mediated Apoptosis. J. Biol. Chem. 283: 21394-21403 [Abstract] [Full Text]  
  • Caporali, S., Levati, L., Starace, G., Ragone, G., Bonmassar, E., Alvino, E., D'Atri, S. (2008). AKT Is Activated in an Ataxia-Telangiectasia and Rad3-Related-Dependent Manner in Response to Temozolomide and Confers Protection against Drug-Induced Cell Growth Inhibition. Mol. Pharmacol. 74: 173-183 [Abstract] [Full Text]  
  • Kim, W.-J., Rajasekaran, B., Brown, K. D. (2007). MLH1- and ATM-dependent MAPK Signaling Is Activated through c-Abl in Response to the Alkylator N-Methyl-N'-nitro-N'-nitrosoguanidine. J. Biol. Chem. 282: 32021-32031 [Abstract] [Full Text]  
  • Brisson, M., Foster, C., Wipf, P., Joo, B., Tomko, R. J. Jr., Nguyen, T., Lazo, J. S. (2007). Independent Mechanistic Inhibition of Cdc25 Phosphatases by a Natural Product Caulibugulone. Mol. Pharmacol. 71: 184-192 [Abstract] [Full Text]  
  • Kawaguchi, T., Yamashita, Y., Kanamori, M., Endersby, R., Bankiewicz, K. S., Baker, S. J., Bergers, G., Pieper, R. O. (2006). The PTEN/Akt Pathway Dictates the Direct {alpha}V{beta}3-Dependent Growth-Inhibitory Action of an Active Fragment of Tumstatin in Glioma Cells In vitro and In vivo. Cancer Res. 66: 11331-11340 [Abstract] [Full Text]  
  • Mirzoeva, O. K., Kawaguchi, T., Pieper, R. O. (2006). The Mre11/Rad50/Nbs1 complex interacts with the mismatch repair system and contributes to temozolomide-induced G2 arrest and cytotoxicity.. Molecular Cancer Therapeutics 5: 2757-2766 [Abstract] [Full Text]  
  • O'Brien, V., Brown, R. (2006). Signalling cell cycle arrest and cell death through the MMR System. Carcinogenesis 27: 682-692 [Abstract] [Full Text]  
  • Panner, A., James, C. D., Berger, M. S., Pieper, R. O. (2005). mTOR Controls FLIPS Translation and TRAIL Sensitivity in Glioblastoma Multiforme Cells. Mol. Cell. Biol. 25: 8809-8823 [Abstract] [Full Text]  
  • Hirose, Y., Katayama, M., Mirzoeva, O. K., Berger, M. S., Pieper, R. O. (2005). Akt Activation Suppresses Chk2-Mediated, Methylating Agent-Induced G2 Arrest and Protects from Temozolomide-Induced Mitotic Catastrophe and Cellular Senescence. Cancer Res. 65: 4861-4869 [Abstract] [Full Text]  
  • Adamson, A. W., Beardsley, D. I., Kim, W.-J., Gao, Y., Baskaran, R., Brown, K. D. (2005). Methylator-induced, Mismatch Repair-dependent G2 Arrest Is Activated through Chk1 and Chk2. Mol. Biol. Cell 16: 1513-1526 [Abstract] [Full Text]  
  • Perfettini, J.-L., Castedo, M., Nardacci, R., Ciccosanti, F., Boya, P., Roumier, T., Larochette, N., Piacentini, M., Kroemer, G. (2005). Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope. JEM 201: 279-289 [Abstract] [Full Text]  
  • Young, L. C., Thulien, K. J., Campbell, M. R., Tron, V. A., Andrew, S. E. (2004). DNA mismatch repair proteins promote apoptosis and suppress tumorigenesis in response to UVB irradiation: an in vivo study. Carcinogenesis 25: 1821-1827 [Abstract] [Full Text]  
  • Caporali, S., Falcinelli, S., Starace, G., Russo, M. T., Bonmassar, E., Jiricny, J., D'Atri, S. (2004). DNA Damage Induced by Temozolomide Signals to both ATM and ATR: Role of the Mismatch Repair System. Mol. Pharmacol. 66: 478-491 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»