HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 31, 21382-21393, August 1, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/31/21382    most recent M709953200v1 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 Wagner, M. W. Articles by Boothman, D. A. Search for Related Content PubMed PubMed Citation Articles by Wagner, M. W. Articles by Boothman, D. A. Social Bookmarking                      What's this?

Role of c-Abl Kinase in DNA Mismatch Repair-dependent G₂ Cell Cycle Checkpoint Arrest Responses^*

Mark W. Wagner¹, Long Shan Li¹, Julio C. Morales, Cristi L. Galindo^¶, Harold R. Garner^¶, William G. Bornmann^||, and David A. Boothman²

From the Laboratory of Molecular Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Comprehensive Cancer Center, and the ^¶McDermott Center for Human Growth and Development, Division of Translational Research, Departments of Biochemistry and Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8807, the Department of Environmental Health Sciences, Case Western Reserve University, Cleveland, Ohio 44106, and the ^||Department of Experimental Therapeutics, M. D. Anderson Cancer Center, Houston, Texas 77030

Current published data suggest that DNA mismatch repair (MMR) triggers prolonged G₂ cell cycle checkpoint arrest after alkylation damage from N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) by activating ATR (ataxia telangiectasia-Rad3-related kinase). However, analyses of isogenic MMR-proficient and MMR-deficient human RKO colon cancer cells revealed that although ATR/Chk1 signaling controlled G₂ arrest in MMR-deficient cells, ATR/Chk1 activation was not involved in MMR-dependent G₂ arrest. Instead, we discovered that disrupting c-Abl activity using STI571 (Gleevec^TM, a c-Abl inhibitor) or stable c-Abl knockdown abolished MMR-dependent p73 stabilization, induction of GADD45 protein expression, and G₂ arrest. In addition, inhibition of c-Abl also increased the survival of MNNG-exposed MMR-proficient cells to a level comparable with MMR-deficient cells. Furthermore, knocking down GADD45 (but not p73) protein levels affected MMR-dependent G₂ arrest responses. Thus, MMR-dependent G₂ arrest responses triggered by MNNG are dependent on a human MLH1/c-Abl/GADD45 signaling pathway and activity. Furthermore, our data suggest that caution should be taken with therapies targeting c-Abl kinase because increased survival of mutator phenotypes may be an unwanted consequence.

Received for publication, December 6, 2007 , and in revised form, May 9, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01-CA-83196 from NCI (to D. A. B.). This work was also supported by Grant DE-FG02-06ER64186 from the Department of Energy (to D. A. B.). This is Manuscript CSCN 019 from the Program in Cell Stress and Cancer Nanomedicine, Simmons Comprehensive Cancer Center. 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. 1–4.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Program in Cell Stress and Cancer Nanomedicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., ND2.210K, Dallas, TX 75390-8807. Tel.: 214-645-6371; Fax: 214-645-6347; E-mail: David.Boothman{at}UTSouthwestern.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. S. Li, J. C. Morales, A. Hwang, M. W. Wagner, and D. A. Boothman DNA Mismatch Repair-dependent Activation of c-Abl/p73{alpha}/GADD45{alpha}-mediated Apoptosis J. Biol. Chem., August 1, 2008; 283(31): 21394 - 21403. [Abstract] [Full Text] [PDF]