Intracellular dynamics of Smad-mediated TGFβ signaling
Intracellular dynamics of Smad-mediated TGFβ signaling
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DOI：
10.1002/jcp.10355
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发表时间：
2003-11-01
影响因子：
5.6
通讯作者：
Pisano, MM
中科院分区：
文献类型：
--
作者：
Greene, RM;Nugent, P;Pisano, MM
转化生长因子-β(TGFbeta)家族是一类信号分子，在正常胚胎发育的形态发生、生长和细胞分化过程中发挥核心作用。这个生长因子家族的成员对哺乳动物次级腭部的发育特别重要，在那里它们调节着腭部间充质细胞的增殖和细胞外基质的合成。这种调节尤其重要，因为细胞过程的扰动会导致腭裂。虽然TGFbeta对胚胎头面部组织的细胞和表型影响已经被广泛地编目，但在腭部个体发育过程中作为TGFbeta下游调节因子在胚胎中发挥作用的特定基因却缺乏明确的定义。体内胚胎腭部组织和体外培养的小鼠胚胎腭间充质细胞(MEPM)分泌和反应转化生长因子β(TGFbeta)。在本研究中，在胚胎腭部细胞中鉴定和鉴定了TGFbeta细胞内信号系统的Smad元件，并证实了TGFbeta1、TGFbeta2和TGFbeta3对Smad通路的功能激活。在胚胎腭部细胞中，TGFbeta启动的Smad信号被发现导致：(1)Smad2的磷酸化；(2)Smads 2、3和4蛋白复合体的核易位；(3)Smads 3和4与共同的Smad结合元件(SBE)寡核苷酸结合；(4)包含TGFbeta诱导的Smad反应元件的报告结构的反式激活；以及(4)明胶酶A和B(包含Smad反应元件的内源基因)的表达增加，它们的表达在腭部个体发育过程中对基质重塑至关重要。总而言之，这些数据表明，在发育中的小鼠上颚细胞中存在一个由Smad介导的TGFbeta信号系统。(C)2003年Wiley-Liss，Inc.
The transforming growth factor-beta (TGFbeta) family represents a class of signaling molecules that plays a central role in morphogenesis, growth, and cell differentiation during normal embryonic development. Members of this growth factor family are particularly vital to development of the mammalian secondary palate where they regulate palate mesenchymal cell proliferation and extracellular matrix synthesis. Such regulation is particularly critical since perturbation of either cellular process results in a cleft of the palate. While the cellular and phenotypic effects of TGFbeta on embryonic craniofacial tissue have been extensively catalogued, the specific genes that function as downstream mediators of TGFbeta action in the embryo during palatal ontogenesis are poorly defined. Embryonic palatal tissue in vivo and murine embryonic palate mesenchymal (MEPM) cells in vitro secrete and respond to TGFbeta. In the current study, elements of the Smad component of the TGFbeta intracellular signaling system were identified and characterized in cells of the embryonic palate and functional activation of the Smad pathway by TGFbeta1, TGFbeta2, and TGFbeta3 was demonstrated. TGFbeta-initiated Smad signaling in cells of the embryonic palate was found to result in: (1) phosphorylation of Smad 2; (2) nuclear translocation of the Smads 2, 3, and 4 protein complex; (3) binding of Smads 3 and 4 to a consensus Smad binding element (SBE) oligonucleotide; (4) transactivation of transfected reporter constructs, containing TGFbeta-inducible Smad response elements; and (4) increased expression of gelatinases A and B (endogenous genes containing Smad response elements) whose expression is critical to matrix remodeling during palatal ontogenesis. Collectively, these data point to the presence of a functional Smad-mediated TGFbeta signaling system in cells of the developing murine palate. (C) 2003 Wiley-Liss, Inc.