Bax accelerates tumorigenesis in p53-deficient mice

Bax is a Bcl-2 family member that promotes apoptosis and counters the prote ctive effect of Bcl-2, Bax Is a downstream effector of p53-induced apoptosi s and is transcriptionally regulated by p53. Moreover, the introduction of Bax deficiency accelerates the onset of tumors in transgenic mice expressin g truncated large T antigen, These results implicate Bax as a tumor suppres sor. Consequently, we asked whether the levels of Ban expression would infl uence tumor development by comparing Bax-deficient and Ban 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 oncogenesi s in mice also deficient in p53, We generated Lck(pr)-Bax transgenic mice t o examine the effects of overexpressed BAX on T-cell development and tumori genesis, Lck(pr)-Bax mice show increased apoptosis consistent with the pro- apoptotic function of Bax. The introduction of p53-deficiency did not inter fere with BAX-induced apoptosis; this is consistent with BAX operating down stream or independent of p53, However, we found that Lck(pr)-Bax/p53-defici ent mice have an increased incidence of T-cell lymphomas when compared with p53-deficient mice. The Lck(pr)-Bax transgenic mice have an increased perc entage of cells in cycle. These findings extend previous work suggesting th at Bcl-2 family proteins regulate proliferation as well as cell death, We c onclude that BAX-induced proliferation is synergistic with a defect in apop tosis contributed by p53-deficiency. Thus, the dual roles of BAX can either accelerate or inhibit tumorigenesis depending on the genetic context.