Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways.
Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways.
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发表时间：
1994-06
期刊：
影响因子：
8
通讯作者：
M. Selvakumaran;H. Lin;T. Miyashita;H. G. Wang;S. Krajewski;John Calvin Reed;B. Hoffman;D. Liebermann-D.
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文献类型：
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作者：
M. Selvakumaran;H. Lin;T. Miyashita;H. G. Wang;S. Krajewski;John Calvin Reed;B. Hoffman;D. Liebermann-D.
最近，促进细胞存活的Bcl-2和促进细胞死亡的Bax都被认为是控制凋亡途径的主要参与者，并且已经表明Bcl-2和Bax蛋白的比例控制细胞对死亡刺激的相对易感性。我们使用M1髓性白血病细胞和基因工程M1变体作为模型系统来研究由两种不同的凋亡刺激物诱导的凋亡。这包括通过激活在M1细胞中表达的温度敏感性p53转基因的野生型p53功能诱导的凋亡，所述M1细胞不表达内源性p53，以及通过TGF β 1诱导的凋亡。结果表明，p53诱导的凋亡动力学比TGF β 1诱导的凋亡更快。还表明，在阻断TGF β 1诱导的M1细胞凋亡的水平上，Bcl-2的异位表达延迟但不阻断p53诱导的凋亡。p53和TGF β 1均下调内源性Bcl-2表达，但仅p53上调Bax表达，其中Bax已被鉴定为p53立即早期反应基因。因此，p53介导的Bax上调至少可以部分解释p53诱导的细胞凋亡速率比TGF β 1更快，以及异位Bcl-2对消除p53介导的细胞凋亡无效。这些研究结果提供了第一次的见解介导p53诱导的细胞凋亡的分子机制，确定bax和bcl-2作为p53调节基因，并作为一个范例，细胞内的平衡Bcl-2 Bax是如何不同的死亡刺激的差异改变。
Recently, both Bcl-2, which promotes cell survival, and Bax, which promotes cell death, have been implicated as major players in the control of apoptotic pathways, and it has been suggested that the ratio of Bcl-2 and Bax protein controls the relative susceptibility of cells to death stimuli. We have used M1 myeloid leukemia cells and genetically engineered M1 variants as a model system to study apoptosis induced by two distinct apoptotic stimuli. This includes apoptosis induced by activation of wild type p53 function of a temperature sensitive p53 transgene expressed in M1 cells, which do not express endogenous p53, and apoptosis induced by TGF beta 1. It is shown that the kinetics of apoptosis 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 blocked TGF beta 1-induced apoptosis of M1 cells, delayed, but did not block, p53-induced apoptosis. Both p53 and TGF beta 1 down-regulated endogenous 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 partial explanation for the more rapid rate of apoptosis induced by p53 compared to by TGF beta 1, as well as for the ineffectiveness of ectopoic Bcl-2 to abrogate p53-mediated apoptosis. These findings provide first insights to the molecular mechanisms which mediate p53-induced apoptosis, 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 differentially altered by distinct death stimuli.