ヨシダ カツノリ   YOSHIDA K.
  吉田 勝紀
   所属   関西医科大学  内科学第三講座
   職種   講師
論文種別 原著(症例報告除く)
言語種別 英語
査読の有無 査読あり
表題 Reversible Smad-dependent signaling between tumor suppression and oncogenesis.
掲載誌名 正式名:Cancer Research
略  称:Cancer Res
ISSNコード:00085472/15387445
巻・号・頁 67(11),pp.5090-5096
著者・共著者 Sekimoto G, Matsuzaki K, Yoshida K, Mori S, Murata M, Seki T, Matsui H, Fujisawa J, Okazaki K
発行年月 2007/06
概要 Cancer cells often gain advantage by reducing the tumor-suppressive activity of transforming growth factor-beta (TGF-beta) together with stimulation of its oncogenic activity as in Ras-transformed cells; however, molecular mechanisms remain largely unknown. TGF-beta activates both its type I receptor (TbetaRI) and c-Jun NH2-terminal kinase (JNK), which phosphorylate Smad2 and Smad3 at the COOH-terminal (pSmad2/3C) and linker regions (pSmad2/3L). Here, we report that Ras transformation suppresses TbetaRI-mediated pSmad3C signaling, which involves growth inhibition by down-regulating c-Myc. Instead, hyperactive Ras constitutively stimulates JNK-mediated pSmad2/3L signaling, which fosters tumor invasion by up-regulating plasminogen activator inhibitor-1 and matrix metalloproteinase-1 (MMP-1), MMP-2, and MMP-9. Conversely, selective blockade of linker phosphorylation by a mutant Smad3 lacking JNK-dependent phosphorylation sites results in preserved tumor-suppressive function via pSmad3C in Ras-transformed cells while eliminating pSmad2/3L-mediated invasive capacity. Thus, specific inhibition of the JNK/pSmad2/3L pathway should suppress cancer progression by shifting Smad-dependent signaling from oncogenesis to tumor suppression.
文献番号 17545585