Inhibition of the janus kinase family increases extracellular signal-regulated kinase 1/2 phosphorylation and causes endoreduplication.
Inhibition of the janus kinase family increases extracellular signal-regulated kinase 1/2 phosphorylation and causes endoreduplication.
复制标题
抑制 janus 激酶家族会增加细胞外信号调节激酶 1/2 磷酸化并导致核内复制。
DOI：
10.1158/0008-5472.can-06-0972
复制
发表时间：
2006
期刊：
影响因子：
11.2
通讯作者：
Yen,Andrew
中科院分区：
文献类型：
--
作者：
Reiterer,Gudrun;Yen,Andrew
在HL-60成髓细胞白血病细胞中确定Janus激活激酶（JAK）信号传导在细胞周期转运和维持基因组稳定性中的作用。JAK、所有JAK（JAK 1、JAK 2、JAK 3和酪氨酸激酶2）、JAK 2或JAK 3的抑制导致细胞生长显著减少，处理后24小时明显出现主要的G2-M期阻滞。靶向所有JAK也在治疗后48和72小时引起核内复制。我们发现有丝分裂细胞在G2（4 N DNA）和G4（8 N DNA）亚群的细胞处理与抑制剂的所有JAK检测磷酸化组蛋白H3的表达。仅用JAK 2或JAK 3的抑制剂处理显著减少了这种有丝分裂细胞。我们观察到当所有JAK被抑制时，IFN-γ和白细胞介素-6诱导的信号转导和转录激活因子（STAT）-1和STAT-3反应被完全阻断。与此同时，我们发现JAK抑制可使基线磷酸化细胞外信号调节激酶（ERK）1/2升高，特别是当所有JAK均被抑制时。在用PD 98059预处理以抑制ERK的细胞中，JAK抑制剂诱导的G2-M期阻滞和核内复制减少。PD 98059还增加了MAD 2细胞周期检查点蛋白的表达，该蛋白在“所有JAK抑制剂”介导的核内复制期间被下调。这些数据表明，JAK信号传导是需要的G2-M转运与ERK的抑制。（Cancer Res 2006; 66（18）：9083-9）（Cancer Res 2006; 66（18）：9083-9）
The role of Janus-activated kinase (JAK) signaling in cell cycle transit and maintenance of genomic stability was determined in HL-60 myeloblastic leukemia cells. Inhibition of JAKs, all JAKs (JAK1, JAK2, JAK3, and tyrosine kinase 2), JAK2, or JAK3, caused a significant reduction in cell growth with a major G2-M arrest evident 24 hours after treatment. Targeting all JAKs also caused endoreduplication 48 and 72 hours after treatment. We discovered mitotic cells in both G2 (4N DNA) and G4 (8N DNA) subpopulations of cells treated with an inhibitor of all JAKs as detected by phosphorylated histone H3 expression. Treatment with inhibitors of just JAK2 or JAK3 drastically reduced such mitotic cells. We observed a complete blockage of IFN-γ and interleukin-6-induced signal transducer and activator of transcription (STAT)-1 and STAT-3 response when all JAKs were inhibited. At the same time, we found baseline phosphorylated extracellular signal-regulated kinase (ERK) 1/2 to be elevated by JAK inhibition, particularly when all JAKs were inhibited. The G2-M arrest and endoreduplication induced by JAK inhibitors were reduced in cells pretreated with PD98059 to inhibit ERK. PD98059 also increased back the expression of the MAD2 cell cycle checkpoint protein that was down-regulated during “all JAKs inhibitor”–mediated endoreduplication. These data suggest that JAK signaling is needed for G2-M transit with inhibition of ERK. (Cancer Res 2006; 66(18): 9083-9) (Cancer Res 2006; 66(18): 9083-9)