T cells from bax alpha transgenic mice show accelerated apoptosis in response to stimuli but do not show restored DNA damage-induced cell death in the absence of p53

Bax alpha was isolated due to its interaction with Bcl-2. Bax alpha overexpression in an interleukin (IL)-3 dependent cell line accelerates apoptosis upon removal of the cytokine, The ratio of Bax alpha to Bcl-2 appears to be crucial for the effect, To study the action of the bax gene product in vivo, we have generated transgenic mice overexpressing Bax alpha specifically in T cells. Such T cells show accelerated apoptosis in response to gamma-radiation, dexamethasone and etoposide, By crossing bax alpha mice with bcl-2 transgenics we show that the critical nature of the Bax alpha:Bcl-2 ratio holds in primary T cells and that it can be manipulated to elicit a strong response to previously resisted stimuli, p53 has a role in the regulation of apoptosis in response to DNA-damaging agents. p53 directly activates transcription of the bax gene. The presence of the bax alpha transgene accelerated apoptosis in thymocytes from both p53-/- and p53+/- mice in response to dexamethasone. Thymocytes from p53-/- mice with the bax alpha transgene showed similar resistance to apoptosis by DNA-damaging agents as did p53-/- mice without the transgene. Bax alpha overexpression alone cannot restore the DNA damage apoptosis pathway, suggesting that p53 is required to induce or activate other factor(s) to reconstitute the response fully.