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Biological functions and signaling pathways mediated by gp130, a signal-transducing receptor component shared by the IL-6 family of cytokines.

gp130 介导的生物功能和信号传导途径，gp130 是 IL-6 细胞因子家族共有的信号转导受体成分。

基本信息

批准号：
10480198
负责人：
TAGA Tetsuya
金额：
$ 7.3万
依托单位：
Kumamoto University (2000)Tokyo Medical and Dental University (1998-1999)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

gp130 is a signal-transducing receptor component shared by the interleukin-6 (IL-6) family of cytokines, i.e. IL-6, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OSM), and cardiotrophin-1 (CT-1). In this project, we have found that mice deficient for gp130 exhibit loss of motor neurons in the spinal cord, nucleus ambiguus and facial nucleus as well as sensory neurons in the dorsal root ganglions. The loss of neurons in the gp130 knock-out mice is prominent on embryonic day 18.5 but not 14.5, suggesting that gp130 is important for the survival and maintenance of neurons but not their differentiation. We have also found that signals from gp130 and bone morphogenetic protein (BMP) receptors act in synergy on fetal brain neural progenitor cells to induce astrocyte differentiation. For instance, LIF and BMP2 synergistically induce astrocytes in cultured neuroepithelial cells. The molecular basis proposed by us is that respective downstream transcription factors, STAT3 and Smads, form a complex bridged by a transcriptional coactivator p300. Another recent finding is that BMP2 inhibits neurogenesis from neural progenitor cells by upregulating expression of negative helix-loop-helix (HLH) factors, Id1, Id3 and Hes-5, which are capable of inhibiting transcriptional activity of neurogenic HLH transcription factors, Mash1 and Neurogenin. In this project, we have also found that MH60 hybridoma cells, which show gp130-signal dependent growth, undergo apoptosis in response to BMP2. Unexpectedly, BMP2-mediated apoptosis is blocked by ectopic expression of inhibitory Smad species, Smad6 and Smad6 binds to a BMP2 downstream kinase TAK1.

gp 130是由细胞因子的白细胞介素-6（IL-6）家族，即IL-6、IL-11、白血病抑制因子（LIF）、睫状神经营养因子（CNTF）、制瘤素M（OSM）和心肌营养素-1（CT-1）共享的信号转导受体组分。在这个项目中，我们发现缺乏gp 130的小鼠表现出脊髓、疑核和面神经核的运动神经元以及背根神经节的感觉神经元的损失。gp 130基因敲除小鼠的神经元损失在胚胎第18.5天而不是第14.5天是突出的，这表明gp 130对神经元的存活和维持是重要的，但不是它们的分化。我们还发现来自gp 130和骨形态发生蛋白（BMP）受体的信号协同作用于胎脑神经祖细胞以诱导星形胶质细胞分化。例如，LIF和BMP 2协同诱导培养的神经上皮细胞中的星形胶质细胞。我们提出的分子基础是，各自的下游转录因子，STAT 3和Smads，形成一个由转录辅激活因子p300桥接的复合物。另一个最近的发现是BMP 2通过上调负螺旋-环-螺旋（HLH）因子Id 1、Id 3和Hes-5的表达来抑制来自神经祖细胞的神经发生，所述负螺旋-环-螺旋（HLH）因子Id 1、Id 3和Hes-5能够抑制神经源性HLH转录因子Mash 1和Neurogenin的转录活性。在这个项目中，我们还发现，MH 60杂交瘤细胞，这表明gp 130信号依赖性的增长，进行凋亡响应BMP 2。出乎意料的是，BMP 2介导的细胞凋亡被抑制性Smad物质Smad 6的异位表达阻断，并且Smad 6结合BMP 2下游激酶TAK 1。