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
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
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DOI：
10.1002/j.1460-2075.1996.tb00463.x
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发表时间：
1996-03-15
期刊：
影响因子：
11.4
通讯作者：
Berns, AJM
中科院分区：
文献类型：
--
作者：
Brady, HJM;Salomons, GS;Berns, AJM
Baxα由于与Bcl2的相互作用而被分离出来。在白介素3依赖的细胞系中过表达Baxα可在去除细胞因子后加速细胞凋亡，Baxα与Bcl2的比例似乎对这一作用至关重要。为了研究Bax基因产物在体内的作用，我们建立了在T细胞中高表达Baxα的转基因小鼠。这类T细胞对伽玛射线、地塞米松和依托泊苷的反应表现出加速的凋亡。通过将baxα与bcl2转基因小鼠杂交，我们证明了baxα：bcl2比率的关键性质在原代T细胞中成立，并且它可以被操纵以引起对先前抵抗的刺激的强烈反应，p53在对DNA损伤剂反应的细胞凋亡的调节中具有作用。P53直接激活Bax基因的转录。Baxα转基因的存在加速了P53-/-和P53+/-小鼠胸腺细胞对地塞米松的反应。来自转Baxα基因的p53-/-小鼠的胸腺细胞对DNA损伤剂诱导的凋亡的抵抗力与未转该基因的p53-/-小鼠相似。BAXα单独过表达不能恢复DNA损伤的细胞凋亡途径，这表明需要P53来诱导或激活其他因子(S)来完全重建反应。
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.