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Molecular and Cellular Biology, November 2001, p. 7653-7662, Vol. 21, No. 22
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.22.7653-7662.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Bax Loss Impairs Myc-Induced Apoptosis and Circumvents the Selection of p53 Mutations during Myc-Mediated Lymphomagenesis

Christine M. Eischen,1,* Martine F. Roussel,2,3 Stanley J. Korsmeyer,4 and John L. Cleveland1,3

Departments of Biochemistry1 and Tumor Cell Biology,2 St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Department of Molecular Sciences, University of Tennessee, Memphis, Tennessee 381633; and Department of Cancer Immunology and AIDS and Howard Hughes Medical Institute, Dana Farber Cancer Institute, Boston, Massachusetts 021154

Received 19 June 2001/Returned for modification 23 July 2001/Accepted 22 August 2001

The ARF and p53 tumor suppressors mediate Myc-induced apoptosis and suppress lymphoma development in Eµ-myc transgenic mice. Here we report that the proapoptotic Bcl-2 family member Bax also mediates apoptosis triggered by Myc and inhibits Myc-induced lymphomagenesis. Bax-deficient primary pre-B cells are resistant to the apoptotic effects of Myc, and Bax loss accelerates lymphoma development in Eµ-myc transgenics in a dose-dependent fashion. Eighty percent of lymphomas arising in wild-type Eµ-myc transgenics have alterations in the ARF-Mdm2-p53 tumor suppressor pathway characterized by deletions in ARF, mutations or deletions of p53, and overexpression of Mdm2. The absence of Bax did not alter the frequency of biallelic deletion of ARF in lymphomas arising in Eµ-myc transgenic mice or the rate of tumorigenesis in ARF-null mice. Furthermore, Mdm2 was overexpressed at the same frequency in lymphomas irrespective of Bax status, suggesting that Bax resides in a pathway separate from ARF and Mdm2. Strikingly, lymphomas from Bax-null Eµ-myc transgenics lacked p53 alterations, whereas 27% of the tumors in Bax+/- Eµ-myc transgenic mice contained p53 mutations or deletions. Thus, the loss of Bax eliminates the selection of p53 mutations and deletions, but not ARF deletions or Mdm2 overexpression, during Myc-induced tumorigenesis, formally demonstrating that Myc-induced apoptotic signals through ARF/Mdm2 and p53 must bifurcate: p53 signals through Bax, whereas this is not necessarily the case for ARF and Mdm2.

* Corresponding author. Present address: The Eppley Institute for Cancer Research, 986805 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-6805. Phone: (402) 559-3894. Fax: (402) 559-3739. E-mail: ceischen{at}unmc.edu.

Molecular and Cellular Biology, November 2001, p. 7653-7662, Vol. 21, No. 22
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.22.7653-7662.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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