Horiguchi Kana, Shirakihara Takuya, Nakano Ayako, Imamura Takeshi, Miyazono Kohei, Saitoh Masao
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 and the Department of Biochemistry, the Cancer Institute of the Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan.
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 and the Department of Biochemistry, the Cancer Institute of the Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan.
J Biol Chem. 2009 Jan 2;284(1):245-253. doi: 10.1074/jbc.M804777200. Epub 2008 Nov 14.
The epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during the progression of epithelial tumors. EMT can be induced by transforming growth factor (TGF)-beta in some tumor cells. Here, we demonstrate the molecular mechanism whereby Snail, a key regulator of EMT, is induced by TGF-beta in tumor cells. Snail induction by TGF-beta was highly dependent on cooperation with active Ras signals, and silencing of Ras abolished Snail induction by TGF-beta in pancreatic cancer Panc-1 cells. Transfection of constitutively active Ras into HeLa cells led to induction of Snail by TGF-beta, while representative direct targets of TGF-beta, including Smad7 and PAI-1, were not affected by Ras signaling. Using mitogen-activated protein kinase inhibitors or Smad3 or Smad2 mutants, we found that phosphorylation at the linker region of Smad2/3 was not required for the induction of Snail by TGF-beta. Taken together, these findings indicate that Ras and TGF-beta-Smad signaling selectively cooperate in the induction of Snail, which occurs in a Smad-dependent manner, but independently of phosphorylation at the linker region of R-Smads by Ras signaling.
上皮-间质转化（EMT）是上皮性肿瘤进展过程中发生的一个关键形态学事件。在某些肿瘤细胞中，EMT可由转化生长因子（TGF）-β诱导。在此，我们阐述了肿瘤细胞中TGF-β诱导EMT关键调节因子Snail的分子机制。TGF-β诱导Snail高度依赖于与活性Ras信号的协同作用，在胰腺癌Panc-1细胞中，沉默Ras可消除TGF-β对Snail的诱导作用。将组成型活性Ras转染到HeLa细胞中可导致TGF-β诱导Snail，而TGF-β的代表性直接靶标，包括Smad7和PAI-1，不受Ras信号影响。使用丝裂原活化蛋白激酶抑制剂或Smad3或Smad2突变体，我们发现TGF-β诱导Snail并不需要Smad2/3连接区的磷酸化。综上所述，这些发现表明Ras与TGF-β-Smad信号在诱导Snail过程中选择性协同作用，该过程以Smad依赖的方式发生，但独立于Ras信号对R-Smads连接区的磷酸化作用。
