Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Maki K, Ogawa S, Chiba S, Mitani K, Hirai H
Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Oncogene. 2001 Jan 4;20(1):88-96. doi: 10.1038/sj.onc.1204057.
The Smad family proteins are critical components of the transforming growth factor (TGF)-beta signaling pathway. TGF-beta is a multipotent cytokine that elicits many biological functions. In particular, TGF-beta exhibits effects on the cell cycle manifested by G1-phase arrest, differentiation, or apoptosis of several target cells, suggesting that disruption of TGF-beta signaling pathway could be involved in cancer formation. Here we show one missense mutation of the Smad4 gene in the MH1 domain (P102L) and one frame shift mutation resulting in termination in the MH2 domain (Delta(483 - 552)) in acute myelogeneous leukemia. Both of the mutated Smad4 proteins lack transcriptional activities. Concomitant expression of the P102L mutant with wild-type Smad4 inactivates wild-type Smad4 through inhibiting its DNA-binding ability. The Delta(483 - 552) mutant blocks nuclear translocation of wild-type Smad4 and thus disrupts TGF-beta signaling. This is the first report showing that mutations in the Smad4 gene are associated with the pathogenesis of acute myelogeneous leukemia and the obtained results should provide useful insights into the mechanism whereby disruption of TGF-beta signaling pathway could lead to acute myelogeneous leukemia. Oncogene (2001) 20, 88 - 96.
Smad家族蛋白是转化生长因子（TGF）-β信号通路的关键组成部分。TGF-β是一种多能细胞因子，可引发多种生物学功能。特别是，TGF-β对细胞周期具有影响，表现为G1期阻滞、分化或几种靶细胞的凋亡，这表明TGF-β信号通路的破坏可能与癌症形成有关。在此，我们展示了急性髓性白血病中Smad4基因在MH1结构域的一个错义突变（P102L）和在MH2结构域导致终止的一个移码突变（Delta(483 - 552)）。两种突变的Smad4蛋白均缺乏转录活性。P102L突变体与野生型Smad4共表达通过抑制其DNA结合能力使野生型Smad4失活。Delta(483 - 552)突变体阻断野生型Smad4的核转位，从而破坏TGF-β信号传导。这是首次报道表明Smad4基因的突变与急性髓性白血病的发病机制相关，所获得的结果应为TGF-β信号通路破坏导致急性髓性白血病的机制提供有用的见解。《癌基因》（2001年）20卷，88 - 96页 。
