Kawabata M, Imamura T, Inoue H, Hanai J, Nishihara A, Hanyu A, Takase M, Ishidou Y, Udagawa Y, Oeda E, Goto D, Yagi K, Kato M, Miyazono K
Department of Biochemistry, Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan.
Ann N Y Acad Sci. 1999;886:73-82. doi: 10.1111/j.1749-6632.1999.tb09402.x.
TGF-beta is a potent inhibitor of cell growth, and accumulating evidence suggests that perturbation of the TGF-beta signaling pathway leads to tumorigenesis. Smads are recently identified proteins that mediate intracellular signaling of the TGF-beta superfamily. Smads 2 and 3 are phosphorylated by the TGF-beta type I receptor. Smad4 was originally identified as a candidate tumor suppressor gene in pancreatic cancers. Smads 2 and 3 form complexes with Smad4 upon TGF-beta stimulation. The heteromeric Smad complexes translocate into the nucleus, where they activate expression of target genes. Our recent study demonstrated that Smads exist as monomers in the absence of TGF-beta. Smads 2 and 3 form homo- as well as hetero-oligomers with Smad4 upon ligand stimulation. Both homo-oligomers and hetero-oligomers directly bind to DNA, suggesting that the signaling pathway of Smads may be multiplex. Smads 2 and 3 associate with transcriptional coactivators such as p300 in a ligand-dependent manner, p300 enhances transactivation by TGF-beta, suggesting that coactivators link Smads to the basal transcriptional machinery. A missense mutation of Smad2 identified in colorectal and lung cancers was introduced to Smad3. The mutant, Smad3(DE), blocked the activation of wild-type Smad2 and Smad3. Thus, the missense mutation not only disrupts the function of the wild-type Smad but also creates a dominant-negative Smad, which could actively contribute to oncogenesis.
转化生长因子-β（TGF-β）是一种强效的细胞生长抑制剂，越来越多的证据表明，TGF-β信号通路的紊乱会导致肿瘤发生。Smads是最近发现的介导TGF-β超家族细胞内信号传导的蛋白质。Smad2和Smad3被TGF-β I型受体磷酸化。Smad4最初被鉴定为胰腺癌中的候选肿瘤抑制基因。在TGF-β刺激下，Smad2和Smad3与Smad4形成复合物。异源Smad复合物转移到细胞核中，在那里它们激活靶基因的表达。我们最近的研究表明，在没有TGF-β的情况下，Smads以单体形式存在。在配体刺激下，Smad2和Smad3与Smad4形成同型和异型寡聚体。同型寡聚体和异型寡聚体都直接与DNA结合，这表明Smads的信号通路可能是多途径的。Smad2和Smad3以配体依赖性方式与转录共激活因子如p300结合，p300增强TGF-β的反式激活作用，这表明共激活因子将Smads与基础转录机制联系起来。在结直肠癌和肺癌中鉴定出的Smad2错义突变被引入到Smad3中。突变体Smad3(DE)阻断了野生型Smad2和Smad3的激活。因此，错义突变不仅破坏了野生型Smad的功能，还产生了一个显性负性Smad，它可能积极促进肿瘤发生。
