Differential regulation of TGF-β signaling through Smad2, Smad3 and Smad4-猫眼课题宝

DOI：

10.1038/sj.onc.1206791

发表时间：

2003-10-02

期刊：

ONCOGENE

影响因子：

8

通讯作者：

中科院分区：

医学1区

文献类型：

--

作者：

Kretschmer, A;Moepert, K;Klippel, A

Smad转录因子介导转化生长因子-β在多种细胞类型中的生长抑制作用。Smads的突变失活与对转化生长因子-β介导的信号转导失去反应性有关。在这项研究中，我们比较了在相同的细胞背景下，单个Smads对转化生长因子-β诱导的生长抑制和内源性基因表达的贡献。Smad2、Smad3和Smad4的表达通过改进的反义分子被选择性地抑制在具有分化能力的细胞中。我们发现，转化生长因子-β主要通过Smad3介导其对HaCaT角质形成细胞生长的抑制作用。抑制Smad3的表达足以干扰转化生长因子-β诱导的细胞周期停滞，并诱导或抑制内源性细胞周期调节因子。抑制Smad4的表达有部分作用，而抑制Smad2的表达没有作用。通过基因表达分析。Ling，我们在全基因组范围内鉴定了在常规生长条件下受Smad2和Smad3差异调控的转化生长因子-β依赖基因。我们发现Smad2、Smad3和Smad4在不同程度上参与了对转化生长因子-β反应的调节，此外，我们还证明了这些Smad2、Smad3和Smad4在不同的细胞类型中表现出不同的作用。

Smad transcription factors mediate the growth inhibitory effect of transforming growth factor-beta (TGF-beta) in many cell types. Mutational inactivation of Smads has been correlated with loss of responsiveness to TGF-beta-mediated signal transduction. In this study, we compare the contribution of individual Smads to TGF-beta-induced growth inhibition and endogenous gene expression in isogenic cellular backgrounds. Smad2, Smad3 and Smad4 expression were selectively inhibited in differentiation-competent cells by using improved antisense molecules. We found that TGF-beta mediates its inhibitory effect on HaCaT keratinocyte cell growth predominantly through Smad3. Inhibition of Smad3 expression was sufficient to interfere with TGF-beta-induced cell cycle arrest and to induce or suppress endogenous cell cycle regulators. Inhibition of Smad4 expression exhibited a partial effect, whereas inhibition of Smad2 expression had no effect. By gene expression pro. ling, we identified TGF-beta-dependent genes that are differentially regulated by Smad2 and Smad3 under regular growth conditions on a genome-wide scale. We show that Smad2, Smad3 and Smad4 contribute to the regulation of TGF-beta responses to varying extents, and demonstrate, in addition, that these Smads exhibit distinct roles in different cell types.