BCL-2 BLOCKS P53-DEPENDENT APOPTOSIS

Adenovirus E1A expression recruits primary rodent cells into prolifera tion but fails to transform them because of the induction of programme d cell death (apoptosis). The adenovirus E1B 19,000-molecular-weight p rotein (19K protein), the E1B 55K protein, and the human Bcl-2 protein each cause high-frequency transformation when coexpressed with E1A by inhibiting apoptosis. Thus, transformation of primary rodent cells by EIA requires deregulation of cell growth to be coupled to suppression of apoptosis. The product of the p53 tumor suppressor gene induces ap optosis in transformed cells and is required for induction of apoptosi s by E1A. The ability of Bcl-2 to suppress apoptosis induced by E1A su ggested that Bcl-2 may function by inhibition of p53. Rodent cells tra nsformed with E1A plus the p53(Val-135) temperature-sensitive mutant a re transformed at the restrictive temperature and undergo rapid and co mplete apoptosis at the permissive temperature when p53 adopts the wil d-type conformation. Human Bcl-2 expression completely prevented p53-m ediated apoptosis at the permissive temperature and caused cells to re main in a predominantly growth-arrested state. Growth arrest was leaky , occurred at multiple points in the cell cycle, and was reversible. B cl-2 did not affect the ability of p53 to localize to the nucleus, nor were the levels of the p53 protein altered. Thus, Bcl-2 diverts the a ctivity of p53 from induction of apoptosis to induction of growth arre st, and it is thereby identified as a modifier of p53 function. The ab ility of Bcl-2 to bypass induction of apoptosis by p53 may contribute to its oncogenic and antiapoptotic activity.