Abounader R, Ranganathan S, Kim B Y, Nichols C, Laterra J
Department of Neuroscience, Kennedy Krieger Research Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Neurochem. 2001 Mar;76(5):1497-508. doi: 10.1046/j.1471-4159.2001.00158.x.
Scatter factor/hepatocyte growth factor (SF/HGF) and its tyrosine kinase receptor c-met are developmentally expressed, neuroprotective, and tumorigenic within the CNS. In the present study SF/HGF is shown to induce the expression of c-met in two human glioblastoma cell lines, U-373 MG and T98G, and the signaling pathways involved in this induction are dissected. SF/HGF activated mitogen-activated protein kinase (MAPK) and inhibition of either Ras or MAPK-kinase completely inhibited SF/HGF-mediated c-met induction. Inhibition of phospholipase-C (PLC) did not affect c-met induction in either cell line. Inhibition of phosphoinositide 3-kinase (PI3-kinase) substantially reduced c-met induction by SF/HGF in T98G cells but had no effect in U-373 MG cells. Protein kinase C (PKC) inhibition reduced c-met induction in T98G cells but not in U-373 MG cells. SF/HGF induced the expression of c-fos and c-jun mRNA and increased the levels of AP-1 transcription factor in both cells lines as determined by AP-1-luciferase reporter expression. Transfection of either cell line with TAM-67, a dominant negative for the jun transactivation domain, completely inhibited AP-1 and c-met induction by SF/HGF. These results support a model of c-met induction by SF/HGF in human glioma cells that uniformly involves Ras, MAPK, and AP-1 and additionally involves PI3-kinase and PKC in some cell lines.
散射因子/肝细胞生长因子（SF/HGF）及其酪氨酸激酶受体c-met在中枢神经系统（CNS）发育过程中表达，具有神经保护作用且具有致瘤性。在本研究中，SF/HGF被证明可诱导两种人胶质母细胞瘤细胞系U-373 MG和T98G中c-met的表达，并对参与该诱导过程的信号通路进行了剖析。SF/HGF激活丝裂原活化蛋白激酶（MAPK），抑制Ras或MAPK激酶可完全抑制SF/HGF介导的c-met诱导。抑制磷脂酶C（PLC）对两种细胞系中c-met的诱导均无影响。抑制磷酸肌醇3激酶（PI3激酶）可显著降低T98G细胞中SF/HGF对c-met的诱导，但对U-373 MG细胞无影响。蛋白激酶C（PKC）抑制可降低T98G细胞中c-met的诱导，但对U-373 MG细胞无影响。通过AP-1荧光素酶报告基因表达测定，SF/HGF诱导了两种细胞系中c-fos和c-jun mRNA的表达，并增加了AP-1转录因子的水平。用TAM-67（一种对jun反式激活结构域具有显性负性作用的蛋白）转染任一细胞系，可完全抑制SF/HGF对AP-1和c-met的诱导。这些结果支持了一种SF/HGF诱导人胶质瘤细胞中c-met表达的模型，该模型一致涉及Ras、MAPK和AP-1，并且在某些细胞系中还涉及PI3激酶和PKC。
