c-Jun N-terminal kinase (JNK) is required for survival and proliferation of B-lymphoma cells
c-Jun N-terminal kinase (JNK) is required for survival and proliferation of B-lymphoma cells
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DOI：
10.1182/blood-2004-10-3819
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发表时间：
2005-08-15
期刊：
影响因子：
20.3
通讯作者：
Bondada, S
中科院分区：
文献类型：
--
作者：
Gururajan, M;Chui, R;Bondada, S
一些原发的小鼠和人B淋巴瘤和细胞系结构性地表达高水平的活化形式的c-jun氨基末端激酶(JNK)，它是丝裂原活化蛋白(MAP)激酶家族的成员。JNK抑制剂SP600125对小鼠B淋巴瘤CH31、CH12.Lx、BKS-2和WEHI-231以及人B淋巴瘤BJAB、Ramos、Raji、OCI-Ly7和OCI-Ly10的增殖均有明显的抑制作用，且呈剂量依赖关系。淋巴瘤细胞发生凋亡，停滞于细胞周期的G(2)/M期。此外，JNK特异性小干扰iRNA(SiRNA)可抑制小鼠和人B淋巴瘤的生长。因此，在B淋巴瘤模型中，JNK似乎具有独特的生存作用。CD40和白介素10(IL-10)提供的生存信号共同逆转了JNK抑制剂诱导的生长抑制。在同时存在SP600125和JNK特异性siRNA的情况下，c-Myc蛋白水平降低，CD40结扎使c-Myc蛋白水平恢复。此外，Bclxl还可使WEHI-231细胞免于JNK抑制剂诱导的细胞凋亡。JNK抑制剂还降低了早期生长反应基因-1(Egr-1)的蛋白水平，过度表达Egr-1部分挽救了淋巴瘤细胞的凋亡。因此，JNK可能通过c-Myc和Egr-1发挥作用，而c-Myc和Egr-1对B淋巴瘤的生存和生长具有重要作用。
Several primary murine and human B lymphomas and cell lines were found to constitutively express high levels of the activated form of c-jun N-terminal kinase (JNK), a member of the mitogen-activated protein (MAP) kinase family. Proliferation of murine B lymphomas CH31, CH12.Lx, BKS-2, and WEHI-231 and the human B lymphomas BJAB, RAMOS, RAJI, OCI-Ly7, and OCI-Ly10 was strongly inhibited by SP600125, an anthrapyrazolone inhibitor of JNK, in a dose-dependent manner. The lymphoma cells underwent apoptosis and arrested at the G(2)/M phase of cell cycle. Furthermore, JNK-specific small interfering IRNA (siRNA) inhibited the growth of both murine and human B lymphomas. Thus in the B-lymphoma model, JNK appears to have a unique prosurvival role. Survival signals provided by CD40 and interieukin-10 (IL-10) together reversed the growth inhibition induced by the JNK inhibitor. c-Myc protein levels were reduced in the presence of both SP600125 and JNK-specific siRNA, and CD40 ligation restored c-Myc levels. Moreover, Bcl-xL rescued WEHI-231 cells from apoptosis induced by the JNK inhibitor. The JNK inhibitor also reduced levels of early growth response gene-1 (Egr-1) protein, and overexpressing Egr-1 partially rescued lymphoma cells from apoptosis. Thus, JNK may act via c-Myc and Egr-1, which were shown to be important for B-lymphoma survival and growth.