IMMEDIATE-EARLY UP-REGULATION OF BAX EXPRESSION BY P53 BUT NOT TGF-BETA-1 - A PARADIGM FOR DISTINCT APOPTOTIC PATHWAYS

Recently, both Bcl-2, which promotes cell survival, and Bax, which pro motes cell death, have been implicated as major players in the control of apoptotic pathways, and it has been suggested that the ratio of Bc l-2 and Bax protein controls the relative susceptibility of cells to d eath stimuli. We have used M1 myeloid leukemia cells and genetically e ngineered M1 variants as a model system to study apoptosis induced by two distinct apoptotic stimuli. This includes apoptosis induced by act ivation of wild type p53 function of a temperature sensitive p53 trans gene expressed in M1 cells, which do not express endogenous p53, and a poptosis induced by TGF beta 1. It is shown that the kinetics of apopt osis induced by p53 is more rapid than apoptosis induced by TGF beta 1 . It is also shown that ectopic expression of Bcl-2, at levels which b locked TGF beta 1-induced apoptosis of M1 cells, delayed, but did not block, p53-induced apoptosis. Both p53 and TGF beta 1 down-regulated e ndogenous Bcl-2 expression, but only p53 up-regulated Bax expression, where bax has been identified as a p53 immediate early response gene. Thus, the p53-mediated up-regulation of Bax may provide at least a par tial explanation for the more rapid rate of apoptosis induced by p53 c ompared to by TGF beta 1, as well as for the ineffectiveness of ectopi c Bcl-2 to abrogate p53-mediated apoptosis. These findings provide fir st insights to the molecular mechanisms which mediate p53-induced apop tosis, identifying bax and bcl-2 as p53 regulated genes, and serve as a paradigm of how the intracellular balance of Bcl-2 to Bax is differe ntially altered by distinct death stimuli.