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Analysis of the IL-6-mediated intracellular signaling molecules in myeloma cell growth

骨髓瘤细胞生长中 IL-6 介导的细胞内信号分子分析

基本信息

批准号：
17590999
负责人：
ISHIKAWA Hideaki
金额：
$ 2.24万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590999/
关键词：
myeloma IL-6 signal-transducing molecules Lyn CD45 PI 3-kinase PI3-kinase 質量分析マイクロアレイ IL-6誘導遺伝子

项目摘要

A cytokine, interleukin-6 (IL-6) is a growth factor for human myeloma cells. Upon IL-6 stimulation, signal transducer and activator of transcription (STAT) 3 and extracellular signal-regulated kinase (ERK) 1/2 are activated. We recently found that in myeloma cell lines the activation of both STAT3 and ERK1/2 is not sufficient for the IL-6-induced proliferation, which further requires the activation of the src family protein-tyrosine kinases (PTKs), such as Lyn, associated with the CD45 protein-tyrosine phosphatase (PTP). To explore the molecular mechanism that governs how IL-6 stimulation induces the proliferation of myeloma cells, such as downstream molecules of Lyn, we have established the myeloma cell lines, ILKM2 and ILKM8 overexpressing Lyn. We have found that both the Lyn-overexpressed ILKM2 and ILKM8 have the higher proliferative rate in response to IL-6 than that of their mock counterpart. In contrast, in the absence of IL-6 these Lyn-overexpressed cell lines showed higher susc … More eptibility to cell death. Cell surface expression of IL-6 receptor a and CD45 was not influenced by the Lyn-overexpression. We have also found that the enhanced activation of the phosphatidylinositol 3-kinase (PI3-K) and Akt in the Lyn-overexpressed cells with IL-6, whereas the activation levels of two other major IL-6-responsive molecules, STAT3 and ERK1/2 remained unchanged, indicating that these are the independent signaling pathways of the Lyn-PI3K-Akt. In the Lyn-overexpressed cells, the Lyn PTK seems to be constitutively active because the positive regulatory tyrosine residue in the catalytic domain was highly phosphorylated, while the negative regulatory tyrosine residue in the COOH-terminus was not phosphorylated, presumably due to its dephosphorylation by CD45 PTP. The PI3-K was co-precipitated with Lyn in the immunoprecipitation assay, and specific inhibition of PI3-K or Akt activities by the pharmacologic reagents suppressed the IL-6-induced proliferation of the Lyn-overexpressed cells, suggesting that the activation of the PI3K-Akt pathways associated with the activated Lyn is indeed related to their concomitant augmentation of myeloma cell growth although the downstream signaling molecules are still need to be explicated. Experiments are also underway to clarify the possible mechanisms of the accelerated cell death of the Lyn-overexpressed myeloma cells as a consequence of the IL-6 withdrawal, our work will provide an understanding of Lyn's role in the IL-6 receptor-mediated signaling. Less

白介素6(IL-6)是一种细胞因子，是人骨髓瘤细胞的生长因子。在IL-6刺激下，信号转导和转录激活子(STAT)3和细胞外信号调节激酶(ERK)1/2被激活。我们最近发现，在骨髓瘤细胞系中，STAT3和ERK1/2的激活不足以满足IL-6诱导的增殖，这进一步需要激活与CD45蛋白-酪氨酸磷酸酶(PTP)相关的src家族蛋白酪氨酸激酶(PTKs)，如Lyn。为了探讨IL-6刺激诱导LYN下游分子等骨髓瘤细胞增殖的分子机制，我们建立了过表达LYN的骨髓瘤细胞系ILKM2和ILKM8。我们发现LYN过表达的ILKM2和ILKM8对IL-6的反应都比其模拟的对应细胞具有更高的增殖速度。相反，在缺乏IL-6的情况下，这些过表达LYN的细胞株显示出更高的suc…对细胞死亡的敏感性更高。细胞表面IL-6受体α和CD45的表达不受Lyn过表达的影响。我们还发现，IL-6促进了Lyn细胞中磷脂酰肌醇3-激酶(PI3-K)和Akt的激活，而另外两个主要的IL-6反应分子STAT3和ERK1/2的激活水平没有变化，表明这些是Lyn-PI3K-Akt的独立信号通路。在Lyn过表达的细胞中，Lyn PTK似乎具有结构性活性，因为催化域中的正调控酪氨酸残基被高度磷酸化，而COOH末端的负调控酪氨酸残基没有被磷酸化，这可能是由于它被CD45 PTP去磷酸化所致。在免疫共沉淀实验中，PI3-K与Lyn共沉淀，药物特异性抑制PI3-K或Akt活性可抑制IL-6诱导的Lyn过表达细胞的增殖，提示与激活的Lyn相关的PI3K-Akt通路的激活确实与其伴随的促进骨髓瘤细胞生长有关，尽管下游的信号分子仍有待阐明。为了阐明IL-6停用导致Lyn过度表达的骨髓瘤细胞加速死亡的可能机制，我们的工作将有助于了解Lyn在IL-6受体介导的信号转导中的作用。较少

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

IL-6-induced Bcl6 variant 2 supports IL-6-dependent myeloma cell proliferation and survival through STAT3.

DOI：
10.1016/j.bbrc.2005.09.036
发表时间：
2005-11
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
N. Tsuyama;I. Danjoh;K. Otsuyama;Masanori Obata;H. Tahara;T. Ohta;H. Ishikawa
通讯作者：
N. Tsuyama;I. Danjoh;K. Otsuyama;Masanori Obata;H. Tahara;T. Ohta;H. Ishikawa

A rapid translocation of CD45RO but not CD45RA to lipid rafts in IL-6-induced proliferation in myeloma

IL-6诱导的骨髓瘤增殖中CD45RO而非CD45RA快速易位至脂筏