Cyclin G2 is up-regulated during growth inhibition and B cell antigen receptor-mediated cell cycle arrest
Cyclin G2 is up-regulated during growth inhibition and B cell antigen receptor-mediated cell cycle arrest
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DOI：
10.1074/jbc.272.19.12650
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发表时间：
1997-05-09
影响因子：
4.8
通讯作者：
Wahl, AF
中科院分区：
文献类型：
--
作者：
Horne, MC;Donaldson, KL;Wahl, AF
人细胞周期蛋白G2与其最接近的同源物细胞周期蛋白G1一起定义了新的细胞周期蛋白家族（Horne，M. C.的方法，Goolsby，G. L.，唐纳森，K. L.，Tran，D.，Neubauer，M.，和Wahl，A. F.（1996）J.Biol.Chem.271，6050-6061），细胞周期蛋白G2在免疫系统中高度表达，其中免疫耐受使自身反应性淋巴细胞经历负选择和通过细胞凋亡的克隆缺失。在这里，我们研究了生长抑制信号对不同成熟阶段特异性小鼠B细胞系中细胞周期蛋白G2 mRNA丰度的影响。在用负生长因子、转化生长因子β 1或生长抑制性皮质类固醇地塞米松处理野生型和p53缺失B细胞系后，细胞周期蛋白G2 mRNA水平以时间依赖性方式增加，是对照细胞水平的5-14倍。未刺激的未成熟B细胞系（WEHI-231和CH 31）和未刺激的或IgM B细胞受体（BCR）刺激的成熟B细胞系（BAL-17和CH 12）迅速增殖并表达低水平的细胞周期蛋白G2 mRNA。相反，BCR刺激的未成熟B细胞系经历生长停滞，并且巧合地表现出类似于10倍的细胞周期蛋白G2转录物增加和细胞周期蛋白D2信息减少。用钙离子载体和蛋白激酶C激动剂共刺激WEHI-231和CH 31细胞部分模拟抗IgM刺激，并引起细胞周期蛋白G2 mRNA的强烈上调和细胞周期蛋白D2 mRNA的下调。当用抗IgM抗体攻击时，磷酸肌醇信号传导途径缺陷并因此对BCR刺激诱导的生长停滞具有抗性的WEHI-231信号传导突变体没有显示出细胞周期蛋白G2 mRNA的显著增加或细胞周期蛋白D2 mRNA的显著减少。两种多克隆活化剂脂多糖和可溶性gp 39抑制未成熟B细胞的生长停滞反应，抑制BCR刺激诱导的cyclin G2 mRNA表达。这些结果表明，在小鼠B细胞响应生长抑制刺激细胞周期蛋白G2可能是一个关键的细胞周期进程的负调节。
Human cyclin G2 together with its closest homolog cyclin G1 defines a novel family of cyclins (Horne, M. C., Goolsby, G. L., Donaldson, K. L., Tran, D., Neubauer, M., and Wahl, A. F. (1996) J. Biol. Chem. 271, 6050-6061), Cyclin G2 is highly expressed in the immune system where immunologic tolerance subjects self-reactive lymphocytes to negative selection and clonal deletion via apoptosis. Here we investigated the effect of growth inhibitory signals on cyclin G2 mRNA abundance in different maturation stage-specific murine B cell lines. Upon treatment of wild type and p53 null B cell lines with the negative growth factor, transforming growth factor beta 1, or the growth inhibitory corticosteroid dexamethasone, cyclin G2 mRNA levels were increased in a time-dependent manner 5-14-fold over control cell levels. Unstimulated immature B cell lines (WEHI-231 and CH31) and unstimulated or IgM B cell receptor (BCR)-stimulated mature B cell lines (BAL-17 and CH12) rapidly proliferate and express low levels of cyclin G2 mRNA. In contrast, BCR-stimulated immature B cell lines undergo growth arrest and coincidentally exhibit an similar to 10-fold increase in cyclin G2 transcripts and a decrease in cyclin D2 message. Costimulation of WEHI-231 and CH31 cells with calcium ionophores and protein kinase C agonists partially mimics anti-IgM stimulation and elicits a strong up-regulation of cyclin G2 mRNA and down-regulation of cyclin D2 mRNA. Signaling mutants of WEHI-231 that are deficient in the phosphoinositide signaling pathway and consequently resistant to the BCR stimulus-induced growth arrest did not display a significant increase in cyclin G2 or decrease in cyclin D2 mRNAs when challenged with anti-IgM antibodies, The two polyclonal activators lipopolysaccharide and soluble gp39, which inhibit the growth arrest response of immature B cells, suppressed cyclin G2 mRNA expression induced by BCR stimulation. These results suggest that in murine B cells responding to growth inhibitory stimuli cyclin G2 may be a key negative regulator of cell cycle progression.