Cytokine-driven cell cycling is mediated through Cdc25A.
Cytokine-driven cell cycling is mediated through Cdc25A.
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DOI：
10.1083/jcb.200409099
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发表时间：
2005-06-06
期刊：
影响因子：
--
通讯作者：
Durum SK
中科院分区：
文献类型：
--
作者：
Khaled AR;Bulavin DV;Kittipatarin C;Li WQ;Alvarez M;Kim K;Young HA;Fornace AJ;Durum SK
淋巴细胞是免疫应答的中心介质，需要细胞因子用于存活和增殖。存活信号传导靶向凋亡介质的Bcl-2家族，然而，对烟碱驱动的淋巴细胞增殖的途径知之甚少。在这里，我们表明，苦参碱诱导的细胞周期进程是不是仅仅依赖于细胞周期蛋白依赖性激酶（Cdks）或细胞周期蛋白的合成。相反，我们观察到，在依赖于白细胞介素-3或白细胞介素-7的淋巴细胞系，或依赖于白细胞介素7的初级淋巴细胞中，磷酸酶Cdc 25 A是增殖的关键介质。从依赖性淋巴细胞中撤出IL-7或IL-3激活应激激酶p38 MAPK，其磷酸化Cdc 25 A，诱导其降解。因此，Cdk/细胞周期蛋白复合物保持磷酸化和无活性，并且细胞在诱导凋亡之前停滞。抑制p38 MAPK或表达突变型Cdc 25 A，其中两个p38 MAPK靶位点S75和S123被改变，使细胞对细胞因子撤回具有抗性，恢复Cdk/细胞周期蛋白复合物的活性并驱动细胞周期独立于生长刺激。
Lymphocytes are the central mediators of the immune response, requiring cytokines for survival and proliferation. Survival signaling targets the Bcl-2 family of apoptotic mediators, however, the pathway for the cytokine-driven proliferation of lymphocytes is poorly understood. Here we show that cytokine-induced cell cycle progression is not solely dependent on the synthesis of cyclin-dependent kinases (Cdks) or cyclins. Rather, we observe that in lymphocyte cell lines dependent on interleukin-3 or interleukin-7, or primary lymphocytes dependent on interleukin 7, the phosphatase Cdc25A is the critical mediator of proliferation. Withdrawal of IL-7 or IL-3 from dependent lymphocytes activates the stress kinase, p38 MAPK, which phosphorylates Cdc25A, inducing its degradation. As a result, Cdk/cyclin complexes remain phosphorylated and inactive and cells arrest before the induction of apoptosis. Inhibiting p38 MAPK or expressing a mutant Cdc25A, in which the two p38 MAPK target sites, S75 and S123, are altered, renders cells resistant to cytokine withdrawal, restoring the activity of Cdk/cyclin complexes and driving the cell cycle independent of a growth stimulus.
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DOI：
10.1084/jem.20030735
发表时间：
2003-12-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kondrack RM;Harbertson J;Tan JT;McBreen ME;Surh CD;Bradley LM
通讯作者：
Bradley LM
影响因子：
5.3
作者：
Khaled, AR;Moor, AN;Durum, SK
通讯作者：
Durum, SK
影响因子：
8
作者：
Cheng, NL;Janumyan, YM;Knudson, CM
通讯作者：
Knudson, CM
影响因子：
4.3
作者：
Goloudina, Anastasia;Yamaguchi, Hiroshi;Bulavin, Dmitry V.
通讯作者：
Bulavin, Dmitry V.
影响因子：
64.8
作者：
Falck, J;Mailand, N;Lukas, J
通讯作者：
Lukas, J