BH3-only proteins Puma and Bim are rate-limiting for γ-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo
BH3-only proteins Puma and Bim are rate-limiting for γ-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo
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DOI：
10.1182/blood-2005-04-1595
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发表时间：
2005-12-15
期刊：
影响因子：
20.3
通讯作者：
Villunger, A
中科院分区：
文献类型：
--
作者：
Erlacher, M;Michalak, EM;Villunger, A
许多p53靶基因与DNA损伤诱导的细胞凋亡信号有关，但促凋亡Bcl-2（B细胞白血病2）家族成员的BH 3（Bcl-2同源区[BH] 3）-仅亚组似乎发挥关键的启动作用。在各种类型的培养细胞中，3种仅BH 3蛋白，即Puma（p53上调的细胞凋亡调节剂）、Noxa和Bim（Bcl-2相互作用的细胞死亡介导剂），已显示响应于DNA损伤和用抗癌药物或糖皮质激素治疗而启动p53依赖性以及p53非依赖性细胞凋亡。特别是，Puma或Bim的缺乏使胸腺细胞和成熟淋巴细胞在不同程度上对生长因子戒断、DNA损伤或糖皮质激素体外诱导的死亡不敏感。为了评估这些发现的体内相关性，我们将缺乏Puma，Noxa或Bim的小鼠进行全身γ射线照射或糖皮质激素地塞米松，并将淋巴细胞存活率与野生型和BCL 2转基因小鼠进行比较。Puma或Bcl-2过表达的缺失有效地保护了不同类型的淋巴细胞免受体内γ辐射的影响，Bim的缺失在大多数淋巴细胞中提供了较低但显着的保护，而Noxa缺乏则没有影响。此外，发现Puma和Bim均显著促进糖皮质激素诱导的杀伤。因此，我们的研究结果表明，Puma和Bim是γ射线和糖皮质激素诱导的体内淋巴细胞凋亡的关键启动子。
Numerous p53 target genes have been implicated in DNA damage-induced apoptosis signaling, but proapoptotic Bcl-2 (B-cell leukemia 2) family members of the BH3 (Bcl-2 homolog region [BH] 3)-only subgroup appear to play the critical initiating role. In various types of cultured cells, 3 BH3-only proteins, namely Puma (p53 up-regulated modulator of apoptosis), Noxa, and Bim (Bcl-2 interacting mediator of cell death), have been shown to initiate p53-dependent as well as p53-independent apoptosis in response to DNA damage and treatment with anticancer drugs or glucocorticoids. In particular, the absence of Puma or Bim renders thymocytes and mature lymphocytes refractory to varying degrees to death induced in vitro by growth factor withdrawal, DNA damage, or glucocorticoids. To assess the in vivo relevance of these findings, we subjected mice lacking Puma, Noxa, or Bim to whole-body gamma-radiation or the glucocorticoid dexamethasone and compared lymphocyte survival with that in wild-type and BCL2-transgenic mice. Absence of Puma or Bcl-2 overexpression efficiently protected diverse types of lymphocytes from the effects of gamma-radiation in vivo, and loss of Bim provided lower but significant protection in most lymphocytes, whereas Noxa deficiency had no impact. Furthermore, both Puma and Bim were found to contribute significantly to glucocorticoid-induced killing. Our results thus establish that Puma and Bim are key initiators of gamma-radiation- and glucocorticoid-induced apoptosis in lymphoid cells in vivo.