MAPK inhibitors modulate Smad2/3/4 complex cyto-nuclear translocation in myofibroblasts via Imp7/8 mediation
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  • 作者:Yufeng Jiang ; Chao Wu ; Alex Boye ; Jiajun Wu
  • 关键词:Myofibroblasts ; Imp7/8 ; MAPK inhibitors ; PAI ; 1 ; Smads ; TGF ; β1
  • 刊名:Molecular and Cellular Biochemistry
  • 出版年:2015
  • 出版时间:August 2015
  • 年:2015
  • 卷:406
  • 期:1-2
  • 页码:255-262
  • 全文大小:1,071 KB
  • 参考文献:1.Friedman SL (2010) Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 7:425-36. doi:10.-038/?nrgastro.-010.-7 PubMed View Article
    2.Elpek GO (2014) Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: an update. World J Gastroenterol 20:7260-276. doi:10.-748/?wjg.?v20.?i23.-260 PubMed Central PubMed View Article
    3.Sun Y, Lu Y, Xie L, Deng Y, Li S, Qin X (2015) Interferon gamma polymorphisms and hepatitis B virus-related liver cirrhosis risk in a Chinese population. Cancer Cell Int 15:35. doi:10.-186/?s12935-015-0184-2 PubMed Central PubMed View Article
    4.Matsuzaki K, Murata M, Yoshida K, Sekimoto G, Uemura Y, Sakaida N, Kaibori M, Kamiyama Y, Nishizawa M, Fujisawa J, Okazaki K, Seki T (2007) Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 46:48-7. doi:10.-002/?hep.-1672 PubMed View Article
    5.Cojocariu CE, Trifan AV, G?rleanu I, Stanciu C (2014) Alcoholic liver disease–epidemiology and risk factors. Rev Med Chir Soc Med Nat Iasi 118:910-17PubMed
    6.Yoon HJ, Cha BS (2014) Pathogenesis and therapeutic approaches for non-alcoholic fatty liver disease. World J Hepatol 6:800-11. doi:10.-254/?wjh.?v6.?i11.-00 PubMed Central PubMed View Article
    7.Stickel F (2015) Alcoholic cirrhosis and hepatocellular carcinoma. Adv Exp Med Biol 815:113-30. doi:10.-007/-78-3-319-09614-8_- PubMed View Article
    8.Furukawa F, Matsuzaki K, Mori S, Tahashi Y, Yoshida K, Sugano Y, Yamagata H, Matsushita M, Seki T, Inagaki Y, Nishizawa M, Fujisawa J, Inoue K (2003) p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts. Hepatology 38:879-89. doi:10.-053/?jhep.-003.-0384 PubMed View Article
    9.Yoshida K, Matsuzaki K, Mori S, Tahashi Y, Yamagata H, Furukawa F, Seki T, Nishizawa M, Fujisawa J, Okazaki K (2005) Transforming growth factor-beta and platelet-derived growth factor signal via c-Jun N-terminal kinase-dependent Smad2/3 phosphorylation in rat hepatic stellate cells after acute liver injury. Am J Pathol 166:1029-039PubMed Central PubMed View Article
    10.Boye A, Kan H, Wu C, Jiang Y, Yang X, He S, Yang Y (2015) MAPK inhibitors differently modulate TGF-beta/Smad signaling in HepG2 cells. Tumour Biol. doi:10.-007/?s13277-014-3002-x PubMed
    11.Yang Y, Yang S, Chen M, Zhang X, Zou Y, Zhang X (2008) Compound Astragalus and Salvia miltiorrhiza Extract exerts anti-fibrosis by mediating TGF-beta/Smad signaling in myofibroblasts. J Ethnopharmacol 118:264-70. doi:10.-016/?j.?jep.-008.-4.-12 PubMed View Article
    12.He S, Yang Y, Liu X, Huang W, Zhang X, Yang S, Zhang X (2012) Compound Astragalus and Salvia miltiorrhiza extract inhibits cell proliferation, invasion and collagen synthesis in keloid fibroblasts by mediating transforming growth factor-β/Smad pathway. Br J Dermatol 166:564-74. doi:10.-111/?j.-365-2133.-011.-0674.?x PubMed View Article
    13.Liu X, Yang Y, Zhang X, Xu S, He S, Huang W, Roberts MS (2010) Compound Astragalus and Salvia miltiorrhiza extract inhibits cell invasion by modulating transforming growth factor-beta/Smad in HepG2 cell. J Gastroenterol Hepatol 25:420-26. doi:10.-111/?j.-440-1746.-009.-5981.?x PubMed View Article
    14.Hu X, Rui W, Wu C, He S, Jiang J, Zhang X, Yang Y (2014) Compound Astragalus and Salvia miltiorrhiza extracts suppress hepatocarcinogenesis by modulating transforming growth factor-β/Smad signaling. J Gastroenterol Hepatol 29:1284-291. doi:10.-111/?jgh.-2490 PubMed View Article
    15.Tahashi Y, Matsuzaki K, Date M, Yoshida K, Furukawa F, Sugano Y, Matsushita M, Himeno Y, Inagaki Y, Inoue K (2002) Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury. Hepatology 35:49-1. doi:10.-053/?jhep.-002.-0083 PubMed View Article
    16.He S, Liu X, Yang Y, Huang W, Xu S, Yang S, Zhang X, Roberts MS (2010) Mechanisms of transforming growth factor beta(1)/Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts. Br J Dermatol 162:538-46. doi:10.-111/?j.-365-2133.-009.-9511.?x PubMed View Article
    17.Bae E, Kim SJ, Hong S, Liu F, Ooshima A (2012) Smad3 linker phosphorylation attenuates Smad3 transcriptional activity and TGF-β1/Smad3-induced epithelial-mesenchymal transition in renal epithelial cells. Biochem Biophys Res Commun 427:593-99. doi:10.-016/?j.?bbrc.-012.-9.-03 PubMed View Article
    18.Meng XM, Huang XR, Xiao J, Chung AC, Qin W, Chen HY, Lan HY (2012) Disruption of Smad4 impairs TGF-β/Smad3 and Smad7 transcriptional regulation during renal inflammation and fibrosis in vivo and in vitro. Kidney Int 81:266-79. doi:10.-038/?ki.-011.-27 PubMed View Article
    19.Choi MJ, Song KM, Park JM, Kwon MH, Kwon KD, Park SH, Ryu DS, Ryu JK, Suh JK (2014) Effect of SMAD7 gene overexpression on TGF-β1-induced prof
  • 作者单位:Yufeng Jiang (1)
    Chao Wu (1)
    Alex Boye (1)
    Jiajun Wu (1)
    Jiyu Wang (1)
    Xiaochuan Yang (1)
    Yan Yang (1)

    1. Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei, 230032, China
  • 刊物类别:Biomedical and Life Sciences
  • 刊物主题:Life Sciences
    Biochemistry
    Medical Biochemistry
    Oncology
    Cardiology
  • 出版者:Springer Netherlands
  • ISSN:1573-4919
文摘
Mitogen-activated protein kinase (MAPK) pathway-dependent linker phosphorylation of Smad2/3 and subsequent formation of Smad2/3/4 complex and its nuclear translocation are crucial for dysregulated transforming growth factor beta (TGF)-β/Smad signaling in liver fibrosis. Abrogation of this critical step of TGF-β/Smad signaling leading to liver fibrosis could provide new insights for future therapy, but the mechanisms remain incompletely understood. In pursuit, we investigated the subcellular expression and nuclear trafficking of the rate limiting Smad2/3/4 complex in exogenous TGF-β1-stimulated myofibroblasts (MFBs) using three MAPK-specific inhibitors. Our results showed that exogenous TGF-β1 stimulation of MFBs produced both increased protein expression and nuclear translocation of phosphorylated (p)-Smad2C/L, oncogenic pSmad3L, Smad4, importin7/8 (Imp7/8), and plasminogen activator inhibitor (PAI)-1 (Protein and mRNA), while decreased Smad7 protein expression. However, the MAPK-specific inhibitors differentially reversed these observations; for instance, ERK-specific inhibitor blocked the expression and nuclear translocation of pSmad2C/L, while both JNK and p38-specific inhibitors blocked the expression and nuclear translocation of pSmad2C/L and oncogenic pSmad3L. The MAPK-specific inhibitors had no significant effect on the total protein expression of Smad4, but rather significantly blocked its nuclear translocation. All the MAPK-specific inhibitors restored Smad7 expression and also decreased Imp7/8 and PAI-1 (Protein and mRNA) expression. Evidently, the MAPK-specific inhibitors blocked Smad2/3/4 complex formation via restoration of inhibitory Smad7 expression and blockade of Smad3L phosphorylation, while they blocked nuclear translocation of Smad2/3/4 complex through inhibition of Imp7/8 leading to decreased PAI-1 (Protein and mRNA) expression.

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