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.
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.
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