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J. Biol. Chem., Vol. 283, Issue 31, 21394-21403, August 1, 2008

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DNA Mismatch Repair-dependent Activation of c-Abl/p73/GADD45-mediated Apoptosis^*

Long Shan Li¹, Julio C. Morales¹, Arlene Hwang, Mark W. Wagner, and David A. Boothman²

From the Laboratory of Molecular Stress Responses, Departments of Oncology, Pharmacology, and Radiation Oncology, Program in Cell Stress and Cancer Nanomedicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8807 and the Department of Environmental Health Sciences, Case Western Reserve University, Cleveland, Ohio 44106

Cells with functional DNA mismatch repair (MMR) stimulate G₂ cell cycle checkpoint arrest and apoptosis in response to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). MMR-deficient cells fail to detect MNNG-induced DNA damage, resulting in the survival of "mutator" cells. The retrograde (nucleus-to-cytoplasm) signaling that initiates MMR-dependent G₂ arrest and cell death remains undefined. Since MMR-dependent phosphorylation and stabilization of p53 were noted, we investigated its role(s) in G₂ arrest and apoptosis. Loss of p53 function by E6 expression, dominant-negative p53, or stable p53 knockdown failed to prevent MMR-dependent G₂ arrest, apoptosis, or lethality. MMR-dependent c-Abl-mediated p73 and GADD45 protein up-regulation after MNNG exposure prompted us to examine c-Abl/p73/GADD45 signaling in cell death responses. STI571 (Gleevec^TM, a c-Abl tyrosine kinase inhibitor) and stable c-Abl, p73, and GADD45 knockdown prevented MMR-dependent apoptosis. Interestingly, stable p73 knockdown blocked MMR-dependent apoptosis, but not G₂ arrest, thereby uncoupling G₂ arrest from lethality. Thus, MMR-dependent intrinsic apoptosis is p53-independent, but stimulated by hMLH1/c-Abl/p73/GADD45 retrograde signaling.

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 CA102792-01 from NCI (to D. A. B.). This work was also supported by Grant DE-FG022179-16-18 from the Department of Energy. This is Manuscript CSCN 020 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. 1–6.

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.

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