MEK/ERK-mediated phosphorylation of Bim is required to ensure survival of T and B lymphocytes during mitogenic stimulation.
MEK/ERK-mediated phosphorylation of Bim is required to ensure survival of T and B lymphocytes during mitogenic stimulation.
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DOI：
10.4049/jimmunol.0803853
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发表时间：
2009-07-01
期刊：
影响因子：
--
通讯作者：
Strasser A
中科院分区：
文献类型：
--
作者：
O'Reilly LA;Kruse EA;Puthalakath H;Kelly PN;Kaufmann T;Huang DC;Strasser A
淋巴细胞的存活和死亡由 Bcl-2 家族的促凋亡和抗凋亡成员之间的平衡调节，并且这与细胞周期和分化的控制相协调。 Bim 是 Bcl-2 家族中仅促凋亡的 BH3 成员，可以通过 MEK/ERK 介导的磷酸化进行调节，从而影响其与促存活 Bcl-2 家族成员的结合及其周转。我们研究了小鼠 B 和 T 淋巴细胞在暴露于凋亡刺激后和有丝分裂激活期间的 Bim 修饰。离子霉素或细胞因子戒断治疗导致 BimEL（最丰富的 Bim 亚型）升高。相比之下，在有丝分裂刺激的 T 细胞和 B 细胞中，BimEL 迅速磷酸化，其水平下降。 MEK/ERK 信号传导的药理学抑制剂可阻止 Bim 中的这两种变化，减少增殖并引发有丝分裂原刺激的 T 和 B 细胞的凋亡。值得注意的是，Bim 的丢失阻止了这种细胞杀伤，但没有恢复细胞周期。这些结果表明，在 T 和 B 淋巴细胞的有丝分裂刺激过程中，MEK/ERK 信号传导对于两个不同的过程至关重要，即细胞存活（至少部分地）通过磷酸化和随后的 Bim 抑制介导，以及细胞周期，其独立于 Bim 失活而进行。
Survival and death of lymphocytes is regulated by the balance between pro- and anti-apoptotic members of the Bcl-2 family, and this is coordinated with the control of cell cycling and differentiation. Bim, a pro-apoptotic BH3-only member of the Bcl-2 family, can be regulated by MEK/ERK-mediated phosphorylation, which affects its binding to pro-survival Bcl-2 family members and its turnover. We investigated Bim modifications in mouse B and T lymphoid cells after exposure to apoptotic stimuli and during mitogenic activation. Treatment with ionomycin or cytokine withdrawal caused an elevation in BimEL, the most abundant Bim isoform. In contrast, in mitogenically stimulated T and B cells, BimEL was rapidly phosphorylated and its levels declined. Pharmacological inhibitors of MEK/ERK-signaling prevented both of these changes in Bim, reduced proliferation and triggered apoptosis of mitogen-stimulated T and B cells. Remarkably, loss of Bim prevented this cell killing but did not restore cell cycling. These results show that during mitogenic stimulation of T and B lymphocytes MEK/ERK signaling is critical for two distinct processes, cell survival, mediated (at least in part) through phosphorylation and consequent inhibition of Bim, and cell cycling, which proceeds independently of Bim inactivation.
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影响因子：
4.3
作者：
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通讯作者：
Scherle, PA
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通讯作者：
Strasser, Andreas
影响因子：
15.3
作者：
Enders, A;Bouillet, P;Puthalakath, H;Xu, YK;Tarlinton, DM;Strasser, A
通讯作者：
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