Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 21, Issue 22, Pages 7653-7662Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.21.22.7653-7662.2001
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Funding
- NCI NIH HHS [CA81695, CA76379, CA56819, P30 CA021765, P01 CA071907, CA71907, F32 CA081695, R01 CA076379, CA21765] Funding Source: Medline
- NIDDK NIH HHS [DK44158, R01 DK044158] Funding Source: Medline
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The ARF and p53 tumor suppressors mediate Myc-induced apoptosis and suppress lymphoma development in E mu -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 E mu -myc transgenics in a dose-dependent fashion. Eighty percent of lymphomas arising in wild-type E mu -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 E mu -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 E mu -myc transgenics lacked p53 alterations, whereas 27% of the tumors in Bax(+/-) E mu -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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