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Molecular and Cellular Biology, November 2000, p. 8373-8381, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Absence of Msh2 Alters Abelson Virus Pre-B-Cell Transformation by Influencing p53 Mutation

Jenia Jenab-Wolcott,1,2,3 Daniel Rodriguez-Correa,1 Armin H. Reitmair,4,dagger Tak Mak,4 and Naomi Rosenberg1,5,*

Departments of Pathology1 and Molecular Biology and Microbiology,5 The Immunology Graduate Program,2 and The Medical Scientist Training Program,3 Tufts University School of Medicine, Boston, Massachusetts 02111, and Amgen Institute, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M4X 1K9, Canada4

Received 6 June 2000/Returned for modification 2 August 2000/Accepted 14 August 2000

Defects in DNA mismatch repair predispose cells to the development of several types of malignant disease. The absence of Msh2 or Mlh1, two key molecules that mediate mismatch repair in eukaryotic cells, increases the frequency of mutation and also alters the response of some cells to apoptosis and cell cycle arrest. To understand the way these changes contribute to cancer predisposition, we examined the effects of defective mismatch repair on the multistep process of pre-B-cell transformation by Abelson murine leukemia virus. In this model, primary transformants undergo a prolonged apoptotic crisis followed by the emergence of fully transformed cell lines. The latter event is correlated to a loss of function of the p53 tumor suppressor protein and down-modulation of the p53 regulatory protein p19Arf. Analyses of primary transformants from Msh2 null mice and their wild-type littermates revealed that both types of cells undergo crisis. However, primary transformants from Msh2 null animals recover with accelerated kinetics, a phenomenon that is strongly correlated to the appearance of cells that have lost p53 function. Analysis of the kinetics with which p53 function is lost revealed that this change provides the dominant stimulus for emergence from crisis. Therefore, the absence of mismatch repair alters the molecular mechanisms involved in transformation by affecting a gene that controls apoptosis and cell cycle progression, rather than by affecting these processes directly.

* Corresponding author. Mailing address: SC313, Tufts Medical School, 136 Harrison Ave., Boston, MA 02111. Phone: (617) 636-2143. Fax: (617) 636-0337. E-mail: nrosenbe{at}opal.tufts.edu.

dagger Present address: Department of Biology, Retinoid Research, Allergan, Irvine, CA 92623.

Molecular and Cellular Biology, November 2000, p. 8373-8381, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Zimmerman, R. S., Rosenberg, N. (2008). Changes in p19Arf Localization Accompany Apoptotic Crisis during Pre-B-Cell Transformation by Abelson Murine Leukemia Virus. J. Virol. 82: 8383-8391 [Abstract] [Full Text]  
  • Stoklosa, T., Poplawski, T., Koptyra, M., Nieborowska-Skorska, M., Basak, G., Slupianek, A., Rayevskaya, M., Seferynska, I., Herrera, L., Blasiak, J., Skorski, T. (2008). BCR/ABL Inhibits Mismatch Repair to Protect from Apoptosis and Induce Point Mutations. Cancer Res. 68: 2576-2580 [Abstract] [Full Text]  
  • Sachs, Z., Sharpless, N. E., DePinho, R. A., Rosenberg, N. (2004). p16Ink4a Interferes with Abelson Virus Transformation by Enhancing Apoptosis. J. Virol. 78: 3304-3311 [Abstract] [Full Text]  
  • Gong, L., Unnikrishnan, I., Raghavan, A., Parmar, K., Rosenberg, N. (2004). Active Akt and Functional p53 Modulate Apoptosis in Abelson Virus-Transformed Pre-B Cells. J. Virol. 78: 1636-1644 [Abstract] [Full Text]  
  • Unnikrishnan, I., Rosenberg, N. (2003). Absence of p53 Complements Defects in Abelson Murine Leukemia Virus Signaling. J. Virol. 77: 6208-6215 [Abstract] [Full Text]  
  • Deng, C.-X., Wang, R.-H. (2003). Roles of BRCA1 in DNA damage repair: a link between development and cancer. Hum Mol Genet 12: R113-123 [Abstract] [Full Text]  


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