Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18(INK4c) and IL-6
Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18(INK4c) and IL-6
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DOI：
10.1016/s1074-7613(00)80241-1
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发表时间：
1997-01-01
期刊：
影响因子：
32.4
通讯作者：
ChenKiang, S
中科院分区：
文献类型：
--
作者：
Morse, L;Chen, DQ;ChenKiang, S
细胞周期停滞和细胞死亡与体内B细胞向浆细胞的终末分化密切相关。这一过程在体外通过白介素6(IL-6)刺激含免疫球蛋白G的人B淋巴母细胞而被重演，导致细胞周期有序地停止、分化和凋亡。在终末分化的浆细胞样细胞中，pRb的磷酸化受到抑制，这与D型细胞周期蛋白依赖性蛋白激酶(CDK)抑制剂p18(INK4c)和p21(WAF1/CIP1)的激活有关。CDK6的表达无明显变化。IL-6可迅速激活p18，并显著增强其与CDK6的相关性和细胞周期停滞。P18在对IL-6诱导分化但不退出细胞周期的含IgM的淋巴母细胞中过表达，重组了偶联分化和细胞周期停滞。因此，CDK抑制剂，特别是p18，可能通过抑制CDK6的pRb磷酸化，在晚期B细胞向浆细胞的终末分化过程中发挥关键作用，控制细胞周期停滞和细胞死亡。
Cell cycle arrest and cell death are tightly coupled to terminal differentiation of B cells to plasma cells in vivo. This process was recapitulated in vitro by stimulation of IgG-bearing human B lymphoblastoid cells with interleukin-6 (IL-6), which led to orderly cell cycle arrest, differentiation, and apoptosis. In terminally differentiated plasmacytoid cells, phosphorylation of pRb was suppressed, correlating with the activation of the D-type cyclin-dependent kinase (CDK) inhibitors p18(INK4c) and p21(WAF1/CIP1). The expression of CDK6, however, remained unchanged. Activation of p18 by IL-6 was rapid, concomitant with marked enhancement of its association with CDK6 and cell cycle arrest. Overexpression of p18 in IgM-bearing lymphoblastoid cells, which differentiated in response to IL-6 but did not exit the cell cycle, reconstituted coupled differentiation and cell cycle arrest. Thus, CDK inhibitors, in particular p18, are likely to play a pivotal role in controlling cell cycle arrest and cell death in terminal differentiation of late-stage B cells to plasma cells via inhibition of pRb phosphorylation by CDK6.