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J. Biol. Chem., Vol. 282, Issue 44, 32021-32031, November 2, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/44/32021    most recent M701451200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, W.-J. Articles by Brown, K. D. Search for Related Content PubMed PubMed Citation Articles by Kim, W.-J. Articles by Brown, K. D. Social Bookmarking                      What's this?

MLH1- and ATM-dependent MAPK Signaling Is Activated through c-Abl in Response to the Alkylator N-Methyl-N'-nitro-N'-nitrosoguanidine^*

Wan-Ju Kim, Baskaran Rajasekaran, and Kevin D. Brown¹

From the Department of Biochemistry and Molecular Biology and the University of Florida Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida 32610 and the Department of Molecular Genetics and Biochemistry, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261

N-Methyl-N'-nitro-N'-nitrosoguanidine (MNNG) is a DNA-methylating agent, and deficiency in mismatch repair (MMR) results in lack of sensitivity to this genotoxin (termed alkylation tolerance). A number of DNA damage response pathways are activated in a MMR-dependent manner following MNNG, and several also require ATM kinase activity. Here we show that activation of the transcription factor c-Jun is dependent upon both the MMR component MLH1 and ATM, but not ATR, in response to MNNG. In addition to c-Jun, the upstream MAPKs JNK and MKK4 are also activated in a MLH1- and ATM-dependent manner. We document that c-Jun activation is dependent on the MAPK kinase kinase MEKK1. Additionally, the tyrosine kinase c-Abl is required to activate this signaling cascade and forms a complex with MEKK1 and MLH1. This study indicates that an arm of DNA damage-activated MAPK signaling is activated in an MLH1- and ATM-dependent manner in response to MNNG and perhaps suggests that dysregulation of this signaling is responsible, in part, for alkylation tolerance.

Received for publication, February 20, 2007 , and in revised form, August 29, 2007.

^* This work was supported by National Institutes of Health Grant R01-CA102289 (to K. D. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Florida College of Medicine, 1600 SW Archer Rd., Box 100245, Gainesville, FL 32610. Tel.: 352-273-5458; Fax: 352-392-1445; E-mail: kdbrown1{at}ufl.edu.

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