FOXO Transcription Factors Enforce Cell Cycle Checkpoints and Promote Survival of Hematopoietic Cells after DNA Damage
FOXO Transcription Factors Enforce Cell Cycle Checkpoints and Promote Survival of Hematopoietic Cells after DNA Damage
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DOI：
10.1158/1541-7786.mcr-08-0531
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发表时间：
2009-08-01
影响因子：
5.2
通讯作者：
Quelle, Frederick W.
中科院分区：
文献类型：
--
作者：
Lei, Hong;Quelle, Frederick W.
在正常条件下，PI3K/AKT信号通路参与细胞因子依赖的造血细胞的细胞周期进程，并且绝对需要覆盖这些细胞中DNA损伤诱导的细胞周期停滞检查点。PI3K/AKT的活性也与造血细胞中的CDK2活性相关，提示CDK2的激活可能是该信号通路的一个相关终点。然而，该通路中AKT下游的介体还没有被定义。叉头转录因子O(FOXO)家族受AKT依赖的磷酸化负调控，是影响细胞周期进程的基因的已知调节者。我们发现，增强的FOXO活性复制了PI3K抑制剂在DNA损伤后强制G(1)和G(2)期停滞的效果。相反，在缺乏PI3K活性的细胞中，内源性FOXO蛋白的敲除增加了CDK2的活性，并覆盖了DNA损伤检查点。此外，FOXO活性的丧失导致对顺铂诱导的细胞死亡的敏感性增加，这与面对这种化疗药物造成的DNA损伤时未能阻止细胞周期进展有关。当FOXO3a单独介导时，这些细胞周期停滞依赖于p27的表达，但当内源性FOXO蛋白促进时，也涉及p27不依赖的机制。总之，这些观察表明，FOXO蛋白在造血细胞中加强了DNA损伤诱导的细胞周期停滞。通过细胞因子诱导的PI3K/AKT信号对FOXO活性的抑制足以超越这些DNA损伤诱导的细胞周期检查点，但可能会对造血细胞的活力产生负面影响。(摩尔癌症研究2009；8(8)：1294-303)
The PI3K/AKT signaling pathway contributes to cell cycle progression of cytokine-dependent hematopoietic cells under normal conditions, and it is absolutely required to override DNA damage-induced cell cycle arrest checkpoints in these cells. Phosphatidylinositol-3-kinase (PI3K)/AKT activity also correlates with Cdk2 activity in hematopoietic cells, suggesting that Cdk2 activation may be a relevant end point for this signaling pathway. However, mediators downstream of AKT in this pathway have not been defined. The forkhead transcription factor O (FOXO) family are negatively regulated by AKT-dependent phosphorylation and are known regulators of genes affecting cell cycle progression. We show that enhanced FOXO activity replicates the effect of PI3K inhibitors in enforcing G(1) and G(2) phase arrest after DNA damage. Conversely, knockdown of endogenous FOXO proteins increased Cdk2 activity and overrode DNA damage checkpoints in cells lacking PI3K activity. Moreover, loss of FOXO activity caused an increase in sensitivity to cisplatin-induced cell death, which was associated with failure to arrest cell cycle progression in the face of DNA damage caused by this chemotherapeutic agent. These cell cycle arrests were dependent on p27 expression when mediated by FOXO3a alone, but also involve p27-independent mechanisms when promoted by endogenous FOXO proteins. Together, these observations show that FOXO proteins enforce DNA damage-induced cell cycle arrest in hematopoietic cells. Inhibition of FOXO activity by cytokine-induced PI3K/AKT signaling is sufficient to override these DNA damage-induced cell cycle checkpoints, but may negatively impact hematopoietic cell viability. (Mol Cancer Res 2009;8(8):1294-303)