title: Bax accelerates tumorigenesis in p53-deficient mice.
abstract: Bax is a Bcl-2 family member that promotes apoptosis and counters the protective effect of Bcl-2. Bax is a downstream effector of p53-induced apoptosis and is transcriptionally regulated by p53. Moreover, the introduction of Bax deficiency accelerates the onset of tumors in transgenic mice expressing truncated large T antigen. These results implicate Bax as a tumor suppressor. Consequently, we asked whether the levels of Bax expression would influence tumor development by comparing Bax-deficient and Bax transgenic mice in the presence or absence of p53. We found that Bax-deficient mice did not display an increased incidence of spontaneous cancers when followed for > 1.5 years. In addition, Bax-deficiency did not further accelerate oncogenesis in mice also deficient in p53. We generated Lck(pr)-Bax transgenic mice to examine the effects of overexpressed BAX on T-cell development and tumorigenesis. Lck(pr)-Bax mice show increased apoptosis consistent with the pro-apoptotic function of Bax. The introduction of p53-deficiency did not interfere with BAX-induced apoptosis; this is consistent with BAX operating downstream or independent of p53. However, we found that Lck(pr)-Bax/p53-deficient mice have an increased incidence of T-cell lymphomas when compared with p53-deficient mice. The Lck(pr)-Bax transgenic mice have an increased percentage of cells in cycle. These findings extend previous work suggesting that Bcl-2 family proteins regulate proliferation as well as cell death. We conclude that BAX-induced proliferation is synergistic with a defect in apoptosis contributed by p53-deficiency. Thus, the dual roles of BAX can either accelerate or inhibit tumorigenesis depending on the genetic context.
authors.affiliation: Department of Pathology, University of Iowa College of Medicine, Iowa City 52241, USA. c-knudson@uiowa.edu
authors.forename: C M
authors.initials: CM
authors.lastname: Knudson
authors.forename: G M
authors.initials: GM
authors.lastname: Johnson
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.forename: S J
authors.initials: SJ
authors.lastname: Korsmeyer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D016019:Survival Analysis; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D001973:Bromodeoxyuridine