抑制性Smad蛋白对TGF-β超家族信号转导的调控及其生理意义

Regulation of TGF-β Superfamily Signaling by Inhibitory Smads

转化生长因子-β(transformation growth factor-β,TGF-β)是一类在结构上相关的转化生长因子,目前发现在哺乳动物有超过30个细胞因子可能属于TGF-β超家族。它们广泛参与各种细胞作用,并因此在胚胎发育与维持组织平衡中发挥重要功能。TGF-β超家族可以通过依赖或不依赖Smad蛋白的方式传递信号;其信号转导过程受到多层次的精确调控。其中,抑制性Smad蛋白(inhibitory Smads,I-Smads),包括Smad6和Smad7,是TGF-β/BMP信号转导过程的关键负调控分子,并且介导TGF-β/BMP信号与其它信号转导通路之间的crosstalk。根据生化实验的研究结果,Smad7是TGF-β超家族广谱的抑制剂,而Smad6主要是特异性针对BMP亚家族的。近年来,利用基因敲除、RNA干扰或者转基因的方法,人们对I-Smads的生理作用有了越来越多的了解,同时也发现Smad7与TGF-β介导的生理过程(如细胞增殖与凋亡,免疫监督与心血管发育等)具有紧密的联系。此外,I-Smads还被发现与TGF-β相关疾病密切相关,并有可能成为疾病治疗的靶点。

The transforming growth factor-β （TGF-β） superfamily is a large group of structurally related growth factors, and by now more than 30 members have been identified in mammals. They play pivotal roles in embryonic development and in homeostasis of adult tissues. The TGF-β superfamily cytokines can transduce their signal through Smad-dependent or -independent pathways, and the signaling transduction processes are finely regulated at multiple levels. Inhibitory Smads （I-Smads）, including Smad6 and Smad7, are key negative regulators in TGF-β/BMP pathways, and also function to integrate TGF-β family signals with other cellular signaling pathways. Biochemical experiments have revealed that Smad7 is a general antagonist to all the TGF-β superfamily members, while Smad6 is specific to block BMP signaling. In recent years, the physiologic functions of I-Smads start to become clear by utilizing the approaches of gene knockout, RNA interference or transgenic models. Smad6 seems to mainly regulate BMP-mediated physiological processes, while Smad7 may play a more important role in TGF-β- mediated processes, such as cell proliferation and death, immunity regulation as well as development of the cardiovascular system. The oberservation that I-Smads are closely related to several kinds of diseases indicates that they may be the potential therapeutic targets.