Roscovitine-induced apoptosis in neutrophils and neutrophil progenitors is regulated by the Bcl-2-family members Bim, Puma, Noxa and Mcl-1.
Roscovitine-induced apoptosis in neutrophils and neutrophil progenitors is regulated by the Bcl-2-family members Bim, Puma, Noxa and Mcl-1.
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DOI：
10.1371/journal.pone.0079352
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Häcker G
中科院分区：
文献类型：
--
作者：
Gautam S;Kirschnek S;Wiesmeier M;Vier J;Häcker G
在感染性和非感染性环境中，中性粒细胞(中性粒细胞)的凋亡在确定炎症中起着关键作用。最近的工作表明，细胞周期蛋白依赖性激酶(CDK)的抑制剂，如罗司可汀，可以有效地诱导中性粒细胞凋亡，减轻炎症。利用条件性Hoxb8表达系统，我们检测了Bcl2家族蛋白对罗可维汀诱导的小鼠中性粒细胞和中性粒细胞前体细胞凋亡的影响。BCL-2对罗可维汀诱导的中性粒细胞凋亡有较强的保护作用。单独丢失Bim或Noxa提供了显著的部分保护，而联合丢失Bim和Noxa或Bim和Puma的保护作用仅略大于这种单独丢失。观察到的蛋白质水平唯一的实质性变化是Mcl-1的丢失，Mcl-1不是转录的，并且被蛋白酶体阻断抑制。在祖细胞中，单独失去Bim没有保护作用，但同时失去Bim和Puma却有实质性的保护；令人惊讶的是，单独失去noxa可以看到最强的保护。祖细胞的蛋白表达和Mcl-1调节模式与在分化的中性粒细胞中观察到的非常相似。此外，罗索维汀强烈抑制祖细胞的增殖，与G2/M期细胞的积聚有关。
Neutrophil granulocyte (neutrophil) apoptosis plays a key role in determining inflammation in infectious and non-infectious settings. Recent work has shown that inhibitors of cyclin-dependent kinases (cdk) such as roscovitine can potently induce neutrophil apoptosis and reduce inflammation. Using a conditional Hoxb8-expression system we tested the participation of Bcl-2-family proteins to roscovitine-induced apoptosis in mouse neutrophils and in neutrophil progenitor cells. Bcl-2 strongly protected against roscovitine-induced apoptosis in neutrophils. The isolated loss of either Bim or noxa provided significant, partial protection while protection through combined loss of Bim and noxa or Bim and Puma was only slightly greater than this individual loss. The only substantial change in protein levels observed was the loss of Mcl-1, which was not transcriptional and was inhibited by proteasome blockade. In progenitor cells there was no protection by the loss of Bim alone but substantial protection by the loss of both Bim and Puma; surprisingly, strongest protection was seen by the isolated loss of noxa. The pattern of protein expression and Mcl-1-regulation in progenitor cells was very similar to the one observed in differentiated neutrophils. In addition, roscovitine strongly inhibited proliferation in progenitor cells, associated with an accumulation of cells in G2/M-phase.
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影响因子：
56.9
作者：
Opferman, JT;Iwasaki, H;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
20.3
作者：
Theilgaard-Mönch, K;Jacobsen, LC;Borregaard, N
通讯作者：
Borregaard, N
影响因子：
12.4
作者：
Leitch, A. E.;Lucas, C. D.;Rossi, A. G.
通讯作者：
Rossi, A. G.
影响因子：
16
作者：
Llambi F;Moldoveanu T;Tait SW;Bouchier-Hayes L;Temirov J;McCormick LL;Dillon CP;Green DR
通讯作者：
Green DR
影响因子：
50.3
作者：
Letai, A;Bassik, MC;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ