DNA damage-induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway
DNA damage-induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway
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DOI：
10.1182/blood.v98.3.834
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发表时间：
2001-08-01
期刊：
影响因子：
20.3
通讯作者：
Quelle, FW
中科院分区：
文献类型：
--
作者：
Henry, MK;Lynch, JT;Quelle, FW
造血细胞暴露于DNA损伤剂诱导细胞周期停滞在G1和G2/M检查点。以前，已经表明，DNA损伤诱导的造血细胞生长停滞可以通过用细胞因子生长因子如促红细胞生成素（EPO）或白细胞介素-3（IL-3）治疗来克服。在这里，所需的超越G1和G2/M检查点γ-照射（γ-IR）诱导的精氨酸激活的信号转导途径的特点。使用稳定表达EPO受体（EPO-R）突变体的因子依赖性骨髓细胞，显示去除PI-3 K信号传导所需的最小结构域消除了EPO克服γ-IR诱导的细胞周期停滞的能力。类似地，细胞因子推翻γ-IR诱导的停滞的能力被PI-3 K（LY 294002）的抑制剂或显性阴性Akt的过表达所消除。此外，EPO在表达缺陷性EPO-R突变体的细胞中超越这些检查点的能力可以通过组成型活性Akt的过表达来恢复。因此，PI-3 K/Akt信号传导途径的激活对于DNA损伤诱导的检查点的精氨酸依赖性抑制是必需的。总之，这些发现表明PI-PKIAkt途径在造血细胞中对DNA损伤的生长停滞反应的调节中具有新的作用。(C)2001年，美国血液学会。
Exposure of hematopoietic cells to DNA-damaging agents induces cell-cycle arrest at G1 and G2/M checkpoints. Previously, it was shown that DNA damage-induced growth arrest of hematopoietic cells can be overridden by treatment with cytokine growth factors, such as erythropoietin (EPO) or interleukin-3 (IL-3). Here, the cytokine-activated signaling pathways required to override G1 and G2/M checkpoints induced by gamma -irradiation (,gamma -IR) are characterized. Using factor-dependent myeloid cells stably expressing EPO receptor (EPO-R) mutants, it is shown that removal of a minimal domain required for PI-3K signaling abrogated the ability of EPO to override gamma -IR-induced cell-cycle arrest. Similarly, the ability of cytokines to override gamma -IR-induced arrest was abolished by an inhibitor of PI-3K (LY294002) or by overexpression of dominant-negative Akt. Moreover, the ability of EPO to override these checkpoints in cells expressing defective EPO-R mutants could be restored by overexpression of a constitutively active Akt. Thus, activation of a PI-3K/Akt signaling pathway is required for cytokine-dependent suppression of DNA-damage Induced checkpoints. Together, these findings suggest a novel role for PI-PKIAkt pathways In the modulation of growth arrest responses to DNA damage In hematopoletic cells. (C) 2001 by The American Society of Hematology.