Cell death provoked by loss of interleukin-3 signaling is independent of Bad, Bim, and PI3 kinase, but depends in part on Puma
Cell death provoked by loss of interleukin-3 signaling is independent of Bad, Bim, and PI3 kinase, but depends in part on Puma
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DOI：
10.1182/blood-2006-03-014209
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发表时间：
2006-09-01
期刊：
影响因子：
20.3
通讯作者：
Vaux, David L.
中科院分区：
文献类型：
--
作者：
Ekert, Paul G.;Jabbour, Anissa M.;Vaux, David L.
造血细胞的生长和存活受生长因子和细胞因子如白细胞介素3（IL-3）调节。当去除细胞因子时，依赖于IL-3的细胞通过Bcl-2过表达抑制的机制杀死自己，并且可能由促凋亡Bcl-2家族成员介导。Bad和Bim是2个这样的仅BH 3的Bcl-2家族成员，其被认为是生长因子撤除后细胞凋亡的关键启动子，特别是在IL-3依赖性细胞中。为了测试Bad、Bim和其他促凋亡Bcl-2家族成员在IL-3撤药诱导的细胞凋亡中的作用，我们从缺乏Bad、Bim、Puma、Bad和Bim两者以及Bax和巴克两者的基因的小鼠中产生IL-3依赖性细胞系。令人惊讶的是，Bad不是IL-3停药后细胞死亡所必需的，这表明Bad磷酸化的变化在该系统中的细胞凋亡中仅起次要作用。Bim的缺失也没有影响，但缺乏Puma的细胞存活下来，并在IL-3恢复时形成集落。在存在或不存在IL-3的情况下，PI 3激酶途径的抑制都会促进细胞凋亡，并且不需要Bad、Bim或Puma，这表明IL-3受体生存信号和PI 3激酶生存信号是独立的。
Growth and survival of hematopoietic cells is regulated by growth factors and cytokines, such as interleukin 3 (IL-3). When cytokine is removed, cells dependent on IL-3 kill themselves by a mechanism that is inhibited by overexpression of Bcl-2 and is likely to be mediated by proapoptotic Bcl-2 family members. Bad and Bim are 2 such BH3-only Bcl-2 family members that have been implicated as key initiators in apoptosis following growth factor withdrawal, particularly in IL-3-dependent cells. To test the role of Bad, Bim, and other proapoptotic Bcl-2 family members in IL-3 withdrawal-induced apoptosis, we generated IL-3-dependent cell lines from mice lacking the genes for Bad, Bim, Puma, both Bad and Bim, and both Bax and Bak. Surprisingly, Bad was not required for cell death following IL-3 withdrawal, suggesting changes to phosphorylation of Bad play only a minor role in apoptosis in this system. Deletion of Bim also had no effect, but cells lacking Puma survived and formed colonies when IL-3 was restored. Inhibition of the PI3 kinase pathway promoted apoptosis in the presence or absence of IL-3 and did not require Bad, Bim, or Puma, suggesting IL-3 receptor survival signals and PI3 kinase survival signals are independent.