Lee M, Hwang C, Lee J, Slavkin H, Warburton D
Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Los Angeles, USA.
Am J Physiol. 1997 Aug;273(2 Pt 1):L374-81. doi: 10.1152/ajplung.1997.273.2.L374.
To evaluate signaling interactions, combinations of epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) isoforms were applied to primary fetal mouse lung mesenchymal cells isolated at 16 days of gestation. The three isoforms of TGF-beta had similar mitogenic potentials, as assessed by thymidine incorporation (half-maximal effective concentration approximately 2 ng/ml). However, combined exposure to EGF and TGF-beta yielded an isoform-dependent attenuation of EGF-induced mitogenesis. Combinations of 20 ng/ml EGF and 2 ng TGF-beta 1, TGF-beta 2, or TGF-beta 3 resulted in thymidine incorporation values 0.76, 0.74, and 0.86 times that of EGF alone, respectively; attenuation of EGF mitogenicity, interactions between EGF and TGF-beta isoforms, and differences between isoforms were all statistically significant by analysis of variance. Treatment with TGF-beta isoforms significantly reduced EGF-induced receptor angiotensin II substrate phosphorylation. TGF-beta isoform-specific signaling also significantly attenuated EGF-induced phosphorylation of the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase 2. These results suggest that isoform-specific TGF-beta signaling modulates the EGF signal transduction pathway upstream of MAP kinase.
为了评估信号相互作用，将表皮生长因子（EGF）和转化生长因子-β（TGF-β）亚型的组合应用于妊娠16天时分离的原代胎鼠肺间充质细胞。通过胸腺嘧啶核苷掺入法评估（半数最大有效浓度约为2 ng/ml），TGF-β的三种亚型具有相似的促有丝分裂潜能。然而，EGF和TGF-β联合暴露导致EGF诱导的有丝分裂发生亚型依赖性衰减。20 ng/ml EGF与2 ng TGF-β1、TGF-β2或TGF-β3组合，导致胸腺嘧啶核苷掺入值分别为单独使用EGF时的0.76、0.74和0.86倍；通过方差分析，EGF有丝分裂原性的衰减、EGF和TGF-β亚型之间的相互作用以及亚型之间的差异均具有统计学意义。用TGF-β亚型处理显著降低了EGF诱导的受体血管紧张素II底物磷酸化。TGF-β亚型特异性信号传导也显著减弱了EGF诱导的丝裂原活化蛋白（MAP）激酶细胞外信号调节激酶2的磷酸化。这些结果表明，亚型特异性TGF-β信号传导在MAP激酶上游调节EGF信号转导途径。
