Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-β in human normal lung epithelial cells
Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-β in human normal lung epithelial cells
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DOI：
10.1038/sj.onc.1202052
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发表时间：
1998-10-01
期刊：
影响因子：
8
通讯作者：
Takahashi, T
中科院分区：
文献类型：
--
作者：
Yanagisawa, K;Osada, H;Takahashi, T
小家族成员是转化生长因子- β (tgf - β)超家族的重要细胞内信号元件，参与一系列生物活性。迄今为止，两个高度同源的分子Smad2和Smad3已被确定为tgf - β信号的受体激活Smads，并成为深入研究的焦点，然而，这些tgf - β信号分子之间没有明确的调节或功能差异。在本研究中，我们发现Smad3的表达，而不是其近亲Smad2，在人肺上皮细胞中被tgf - β介导的信号本身下调。tgf - β对Smad3的下调似乎不是由于Smad3 mRNA半衰期的缩短，tgf - β存在时Smad3的组成性表达诱导凋亡细胞死亡，对人肺上皮细胞生长有不利影响，tgf - β存在时Smad2的强制表达也可诱导凋亡细胞死亡，但效率低于Smad3。这些发现首次明确定义了Smad2和Smad3之间的区别，在对tgf - β的表达调节方面观察到定性差异，而Smad2和Smad3在诱导人肺上皮细胞凋亡细胞死亡方面似乎具有定量不同的能力。
Small family members are essential intracellular signaling components of the transforming growth factor-beta (TGF-beta) superfamily involved in a range of biological activities, Two highly homologous molecules, Smad2 and Smad3, have so far been identified as receptor-activated Smads for TGF-beta signaling and have become the focus of intensive studies, However, no definite differences in regulation or function have been established between these TGF-beta signaling molecules. In the present study, we show that the expression of Smad3, but not its close relative, Smad2, is down-regulated by TGF-beta mediated signals themselves in human lung epithelial cells. This down-regulation of Smad3 by TGF-beta treatment did not appear to result from shortening of the half-life of Smad3 mRNA, Constitutive expression of Smad3 in the presence of TGF-beta induced apoptotic cell death, with an adverse effect on the cell growth of human lung epithelial cells, Apoptotic cell death could also be induced by forced expression of Smad2 in the presence of TGF-beta, but less efficiently than by that of Smad3. These findings clearly define the distinctions between Smad2 and Smad3 for the first time in that a qualitative difference was observed with regard to the regulation of their expression in response to TGF-beta, while Smad2 and Smad3 appeared to have quantitatively different capabilities regarding the induction of apoptotic cell death in human lung epithelial cells.