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