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

Abstract

Baxα was isolated due to its interaction with Bcl-2. Baxα overexpression in an interleukin (IL)-3 dependent cell line accelerates apoptosis upon removal of the cytokine. The ratio of Baxα 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 Baxα specifically in T cells. Such T cells show accelerated apoptosis in response to γ-radiation, dexamethasone and etoposide. By crossing baxα mice with bcl-2 transgenics we show that the critical nature of the Baxα: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 bar gene. The presence of the baxα transgene accelerated apoptosis in thymocytes from both p53-/- and p53+/- mice in response to dexamethasone. Thymocytes from p53-/- mice with the baxα transgene showed similar resistance to apoptosis by DNA-damaging agents as did p53-/- mice without the transgene. Baxα 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.