Reciprocal control of forkhead box O 3a and c-myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels
Reciprocal control of forkhead box O 3a and c-myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels
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DOI：
10.4049/jimmunol.172.9.5522
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发表时间：
2004-05-01
影响因子：
4.4
通讯作者：
Sonenshein, GE
中科院分区：
文献类型：
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作者：
Chandramohan, V;Jeay, S;Sonenshein, GE
小鼠WEHI 231未成熟B淋巴瘤细胞的B细胞受体（BCR）结合导致NF-κ B和c-Myc的下降，并诱导p27（Kip 1）细胞周期蛋白依赖性激酶抑制剂，其促进生长停滞和细胞凋亡。最近显示BCR接合在p27增加之前诱导磷脂酰肌醇3-激酶（PI 3 K）/Akt信号传导的下降。由于p27的诱导是由于基因转录的增加，我们研究了叉头盒O（FOXO）转录因子家族的作用，该家族已被证明能有效诱导p27启动子活性。我们证明了PI 3 K或BCR参与的药理学抑制剂导致非活性细胞质水平降低和活性功能性核FOXO 3a增加。相反，PI 3 K/Akt信号的抑制降低了NF-κ B和c-Myc的水平，这已经显示出抑制p27启动子活性。为了测试异位c-Myc对内源性p27水平的影响，制备稳定表达c-Myc或空载体DNA的WEHI 231细胞。异位c-Myc阻断了PI 3 K或BCR结合抑制后p27表达的诱导。因此，p27（Kip 1）通过信号通路的两个分支协调调节，这两个分支在抑制PI 3 K时反向控制：激活剂FOXO 3a的诱导和阻遏物c-Myc的下调。
B cell receptor (BCR) engagement of murine WEHI 231 immature B lymphoma cells leads sequentially to a drop in NF-kappaB and c-Myc, and induction of the p27(Kip1) cyclin-dependent kinase inhibitor, which promotes growth arrest and apoptosis. BCR engagement was recently shown to induce a drop in phosphatidylinositol 3-kinase (PI3K)/Akt signaling, preceding the increase in p27. As induction of p27 is due to an increase in gene transcription, we investigated the role of the Forkhead box O (FOXO) transcription factor family, which has been shown to potently induce p27 promoter activity. We demonstrate that pharmacologic inhibitors of PI3K or BCR engagement lead to decreased inactive cytoplasmic levels and increased active functional nuclear FOXO3a. In contrast, inhibition of PI3K/Akt signaling decreased the levels of NF-kappaB and c-Myc, which has been shown to repress p27 promoter activity. To test the effects of ectopic c-Myc on endogenous p27 levels, WEHI 231 cells stably expressing c-Myc or empty vector DNA were prepared. Ectopic c-Myc blocked the induction of p27 expression upon either inhibition of PI3K or BCR engagement. Thus, p27(Kip1) is coordinately regulated via two arms of a signaling pathway that are inversely controlled upon inhibition of PI3K: induction of the activator FOXO3a and down-regulation of the repressor c-Myc.