Smad phosphoisoform signals in acute and chronic liver injury: Similarities and differences between epithelial and mesenchymal cells

Cell and Tissue Research

Volumn 347, Issue 1, 2012, Pages 225-243

  Matsuzaki, Koichi ^a  

^a KANSAI MEDICAL UNIVERSITY   (Japan)

Author keywords

Hepatic carcinogenesis; JNK; Liver fibrosis; Smad; TGF

Indexed keywords

ACTIVIN; ALPHA SMOOTH MUSCLE ACTIN; ANTHRA[1,9 CD]PYRAZOL 6(2H) ONE; CONNECTIVE TISSUE GROWTH FACTOR; ISOPROTEIN; PLASMINOGEN ACTIVATOR INHIBITOR 1; SMAD PROTEIN; SMAD2 PROTEIN; SMAD3 PROTEIN; SMALL INTERFERING RNA; STRESS ACTIVATED PROTEIN KINASE; TRANSFORMING GROWTH FACTOR BETA; TRANSFORMING GROWTH FACTOR BETA RECEPTOR;

ANTINEOPLASTIC ACTIVITY; CANCER RISK; CARBOXY TERMINAL SEQUENCE; CELL ACTIVATION; COLLAGEN SYNTHESIS; COLORECTAL CANCER; CYTOKINE RESPONSE; CYTOSTASIS; DRUG TARGETING; EPITHELIAL MESENCHYMAL TRANSITION; EXTRACELLULAR MATRIX; FIBROGENESIS; GROWTH INHIBITION; HUMAN; INTRACELLULAR SIGNALING; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; LIVER FIBROSIS; LIVER INJURY; LIVER REGENERATION; MITOGENESIS; MYOFIBROBLAST; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REVIEW; RISK FACTOR; STELLATE CELL; TRANSCRIPTION REGULATION; TUMOR MICROENVIRONMENT;

ACTIVINS; ANIMALS; CARCINOMA, HEPATOCELLULAR; EPITHELIAL CELLS; HUMANS; JNK MITOGEN-ACTIVATED PROTEIN KINASES; LIVER; LIVER DISEASES; LIVER NEOPLASMS; MESODERM; PHOSPHORYLATION; PROTEIN ISOFORMS; SIGNAL TRANSDUCTION; SMAD PROTEINS;

EID: 84859441977     PISSN: 0302766X     EISSN: 14320878     Source Type: Journal    
DOI: 10.1007/s00441-011-1178-6     Document Type: Review

References (139)

1. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499-511 (Pubitemid 38931765)
2. Alarcón C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S, Barlas A, Miller AN, Manova-Todorova K, Macias MJ, Sapkota G, Pan D, Massagué J (2009) Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-β pathways. Cell 139:757-769
3. Arany PR, Rane SG, Roberts AB (2008) Smad3 deficiency inhibits vras- induced transformation by suppression of JNK MAPK signaling and increased farnesyl transferase inhibition. Oncogene 27:2507-2512 (Pubitemid 351521096)
4. Arthur MJ (2000) Fibrogenesis. II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 279:G245-G249
5. Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, Anzano M, Greenwell-Wild T, Wahl SM, Deng C, Roberts AB (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1:260-266 (Pubitemid 129495775)
6. Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115:209-218 (Pubitemid 40385459)
7. Bellam N, Pasche B (2010) TGF-β signaling alterations and colon cancer. Cancer Treat Res 155:85-103
8. Brown JD, DiChiara MR, Anderson KR, Gimbrone MA Jr, Topper JN (1997) MEKK-1, a component of the stress (stress-activated protein kinase/c-Jun N-terminal kinase) pathway, can selectively activate Smad2-mediated transcriptional activation in endothelial cells. J Biol Chem 274:8797-8805 (Pubitemid 29164678)
9. Burch ML, Yang SN, Ballinger ML, Getachew R, Osman N, Little PJ (2010) TGF-β stimulates biglycan synthesis via p38 and ERK phosphorylation of the linker region of Smad2. Cell Mol Life Sci 67:2077-2090
10. Caestecker MP de, Parks WT, Frank CJ, Castagnino P, Bottaro DP, Roberts AB, Lechleider RJ (1998) Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases. Genes Dev 12:1587-1592 (Pubitemid 28299510)
11. Date M, Matsuzaki K, Matsushita M, Sakitani K, Shibano K, Okajima A, Yamamoto C, Ogata N, Okumura T, Seki T, Kubota Y, Kan M, McKeehan WL, Inoue K (1998) Differential expression of transforming growth factor-β and its receptors in hepatocytes and nonparenchymal cells of rat liver after CCl4 administration. J Hepatol 28:572-581 (Pubitemid 28167994)
12. Date M, Matsuzaki K, Matsushita M, Tahashi Y, Sakitani K, Inoue K (2000a) Differential regulation of activin A for hepatocyte growth and fibronectin synthesis in rat liver injury. J Hepatol 32:251-260 (Pubitemid 30093904)
13. Date M, Matsuzaki K, Matsushita M, Tahashi Y, Furukawa F, Inoue K (2000b) Modulation of transforming growth factor β function in hepatocytes and hepatic stellate cells in rat liver injury. Gut 46:719-724 (Pubitemid 30305793)
14. Derynck R, Akhurst RJ (2007) Differentiation plasticity regulated by TGF-β family proteins in development and disease. Nat Cell Biol 9:1000-1004 (Pubitemid 47338137)
15. Derynck R, Miyazono K (2008) The TGF-β signaling. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
16. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-β family signaling. Nature 425:577-584 (Pubitemid 37280136)
17. Dooley S, Hamzavi J, Ciuclan L, Godoy P, Ilkavets I, Ehnert S, Ueberham E, Gebhardt R, Kanzler S, Geier A, Breitkopf K, Weng H, Mertens PR (2008) Hepatocyte-specific Smad7 expression attenuates TGF-β-mediated fibrogenesis and protects against liver damage. Gastroenterology 135:642-659
18. Eddy AA (2009) Serine proteases, inhibitors and receptors in renal fibrosis. Thromb Haemost 101:656-664
19. Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D, Simon RH (1996) Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 97:232-237 (Pubitemid 26021713)
20. El-Serag HB, RudolphKL (2007)Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557-2576 (Pubitemid 46890874)
21. Elsharkawy AM, Mann DA (2007) Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis. Hepatology 46:590-597 (Pubitemid 47344795)
22. Engel ME, McDonnell MA, Law BK, Moses HL (1999) Interdependent SMAD and JNK signaling in transforming growth factor-β-mediated transcription. J Biol Chem 274:37413-37420
23. Fausto N, Campbell JS, Riehle KJ (2006) Liver regeneration. Hepatology 43:S45-S53
24. Felsher DW (2004) Reversibility of oncogene-induced cancer. Curr Opin Genet Dev 14:37-42
25. Friedman SL (2010) Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 7:425
26. FunabaM, Zimmerman CM, Mathews LS (2002)Modulation of Smad2- mediated signaling by extracellular signal-regulated kinase. J Biol Chem 277:41361-41368 (Pubitemid 35257436)
27. 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 38:879-889 (Pubitemid 37221671)
28. Glick AB, Weinberg WC, Wu IH, Quan W, Yuspa SH (1996) Transforming growth factor β 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb. Cancer Res 56:3645-3650 (Pubitemid 26272005)
29. Gotzmann J, Fischer AN, Zojer M, Mikula M, Proell V, Huber H, Jechlinger M, Waerner T, Weith A, Beug H, Mikulits W (2006) A crucial function of PDGF in TGF-β-mediated cancer progression of hepatocytes. Oncogene 25:3170-3185 (Pubitemid 43881558)
30. Gressner OA (2009) Less Smad2 is good for you! A scientific update on coffee's liver benefits. Hepatology 50:970-978
31. Gressner OA, Lahme B, Demirci I, Gressner AM, Weiskirchen R (2007) Differential effects of TGF-β on connective tissue growth factor (CTGF/CCN2) expression in hepatic stellate cells and hepatocytes. J Hepatol 47:699-710 (Pubitemid 47503426)
32. Grimm OH, Gurdon JB (2002) Nuclear exclusion of Smad2 is a mechanism leading to loss of competence. Nat Cell Biol 4:519-522 (Pubitemid 34752438)
33. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883-899
34. Guo X, Wang XF (2009) Signaling cross-talk between TGF-β/BMP and other pathways. Cell Res 19:71-88
35. Ha H, Oh EY, Lee HB (2009) The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases. Nat Rev Nephrol 5:203-211
36. Hamajima H, Ozaki I, Zhang H, Iwane S, Kawaguchi Y, Eguchi Y, Matsuhashi S, Mizuta T, Matsuzaki K, Fujimoto K (2009) Modulation of the transforming growth factor-β1-induced Smad phosphorylation by the extracellular matrix receptor beta1-integrin. Int J Oncol 35:1441-1447
37. Hayashida T, Caestecker M de, Schnaper HW (2003) Cross-talk between ERK MAP kinase and Smad signaling pathways enhances TGF-β-dependent responses in human mesangial cells. FASEB J 17:1576-1578
38. Haybaeck N, Zeller MJ, Wolf A, Weber U, Wagner MO, Kurrer J, Bremer G, Iezzi RG, Clavien PA et al (2009) A lymphotoxindriven pathway to hepatocellular carcinoma. Cancer Cell 16:295-308
39. He G, Karin M (2011) NF-κB and STAT3 - key players in liver inflammation and cancer. Cell Res 21:159-168
40. He S, Liu X, Yang Y, Huang W, Xu S, Yang S, Zhang X, Roberts MS (2010) Mechanisms of transforming growth factor β(1)/Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts. Br J Dermatol 162:538-546
41. Heldin CH, Miyazono K, ten Dijke P (1997) TGF-β signaling from cell membrane to nucleus through SMAD proteins. Nature 390:465-471 (Pubitemid 28013118)
42. Ho J, Cocolakis E, Dumas VM, Posner BI, Laporte SA, Lebrun JJ (2005) The G protein-coupled receptor kinase-2 is a TGF-β-inducible antagonist of TGF-β signal transduction. EMBO J 24:3247-3258 (Pubitemid 41348699)
43. Hong HY, Jeon WK, Bae EJ, Kim ST, Lee HJ, Kim SJ, Kim BC (2010) 14-3-3 Sigma and 14-3-3 zeta plays an opposite role in cell growth inhibition mediated by transforming growth factor-β1. Mol Cells 29:305-309
44. Hu PF, Chen H, Zhong W, Lin Y, Zhang X, Chen YX, Xie WF (2009) Adenovirus-mediated transfer of siRNA against PAI-1 mRNA ameliorates hepatic fibrosis in rats. J Hepatol 51:102-113
45. Inagaki Y, Okazaki I (2007) Emerging insights into transforming growth factor β Smad signal in hepatic fibrogenesis. Gut 56:284-292
46. Hui L, Zatloukal K, Scheuch H, Stepniak E, Wagner EF (2008) Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J Clin Invest 118:3943-3953
47. Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG (2002) Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 110:341-350 (Pubitemid 34847966)
48. Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H, Günter S (2002) Ras and TGF-β cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 156:299-313 (Pubitemid 34839911)
49. Javelaud D, Mauviel A (2005) Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-β: implications for carcinogenesis. Oncogene 24:5742-5750 (Pubitemid 43086134)
50. Jiang W, Zhang Y, Wu H, Zhang X, Gan H, Sun J, Chen Q, Guo M, Zhang Z (2010) Role of cross-talk between the Smad2 and MAPK pathways in TGF-β1-induced collagen IV expression in mesangial cells. Int J Mol Med 26:571-576
51. Kamaraju AK, Roberts AB (2005) Role of Rho/ROCK and p38 MAP kinase pathways in transforming growth factor-β-mediated Smad-dependent growth inhibition of human breast carcinoma cells in vivo. J Biol Chem 280:1024-1036
52. Kawada N (1997) The hepatic perisinusoidal stellate cell. Histol Histopathol 12:1069-1080
53. Kawamata S, Matsuzaki K, Murata M, Seki T, Matsuoka K, Iwao Y, Hibi T, Okazaki K (2011) Oncogenic Smad3 signaling induced by chronic inflammation is an early event in ulcerative colitis-associated carcinogenesis. Inflamm Bowel Dis 17:683-695
54. Kluwe J, Pradere JP, Gwak GY, Mencin A, DeMinicis S, Osterreicher CH, Colmenero J, Bataller R, Schwabe RF (2010) Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. Gastroenterology 138:347-359
55. Kisseleva T, Brenner DA (2008) Fibrogenesis of parenchymal organs. Proc Am Thorac Soc 5:338-342 (Pubitemid 351520684)
56. Kodama Y, Kisseleva T, Iwaisako K, Miura K, Taura K, De Minicis S, Osterreicher CH, Schnabl B, Seki E, Brenner DA (2009) c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice. Gastroenterology 137:1467-1477
57. Koike K (2002) Hepatocarcinogenesis in hepatitis viral infection: lessons from transgenic mouse studies. J Gastroenterol 37:55-64
58. Kogure K, Omata W, Kanzaki M, Zhang YQ, Yasuda H, Mine T, Kojima I (1995) A single intraportal administration of follistatin accelerates liver regeneration in partially hepatectomized rats. Gastroenterology 108:1136-1142
59. Kretzschmar M, Doody J, Timokhina I, Massagué J (1999) A mechanism of repression of TGF-β/Smad signaling by oncogenic Ras. Genes Dev 13:804-816 (Pubitemid 29169840)
60. Kwaan HC, McMahon B (2009) The role of plasminogen-plasmin system in cancer. Cancer Treat Res 148:43-66
61. Lehmann K, Janda E, Pierreux CE, Rytomaa M, Schulze A, McMahon M, Hill CS, Beug H, Downward J (2000) Raf induces TGF-β production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev 14:2610-2622
62. Li F, Zeng B, Chai Y, Cai P, Fan C, Cheng T (2009) The linker region of Smad2 mediates TGF-β-dependent ERK2-induced collagen synthesis. Biochem Biophys Res Commun 386:289-293
63. Lin Q, Chen D, Timchenko NA, Medrano EE (2010) SKI promotes Smad3 linker phosphorylations associated with the tumorpromoting trait of TGF-β. Cell Cycle 9:1684-1689
64. Liu F (2006) Smad3 phosphorylation by cyclin-dependent kinases. Cytokine Growth Factor Rev 17:9-17
65. Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362:1907-1917 (Pubitemid 37518510)
66. Massagué J (2008) TGF-β in cancer. Cell 134:215-230
67. Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F (2004) Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 430:226-231 (Pubitemid 38902433)
68. Matsuura I, Chiang KN, Lai CY, He D,Wang G, Ramkumar R, Uchida T, Ryo A, Lu K, Liu F (2010) Pin1 promotes transforming growth factor-β-induced migration and invasion. J Biol Chem 285:1754-1764
69. Matsuzaki K (2006) Smad3 phosphoisoform-mediated signaling during sporadic human colorectal carcinogenesis. Histol Histopathol 21:645-662
70. Matsuzaki K (2009) Modulation of TGF-β signaling during progression of chronic liver diseases. Front Biosci 14:2923-2934
71. Matsuzaki K, Date M, Furukawa F, Tahashi Y, Matsushita M, Sugano Y, Yamashiki N, Nakagawa T, Seki T, Nishizawa M, Fujisawa J, Inoue K (2000a) Regulatory mechanisms for transforming growth factor β as an autocrine inhibitor in human hepatocellular carcinoma: implications for roles of Smads in its growth. Hepatology 32:218-227 (Pubitemid 30614653)
72. Matsuzaki K, Date M, Furukawa F, Tahashi Y, Matsushita M, Sakitani K, Yamashiki N, Seki T, Saito H, Nishizawa M, Fujisawa J, Inoue K (2000b) Autocrine stimulatory mechanism by transforming growth factor β in human hepatocellular carcinoma. Cancer Res 60:1394-1402 (Pubitemid 30152013)
73. 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 βsignaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 46:48-57 (Pubitemid 47171920)
74. Matsuzaki K, Kitano C, Murata M, Sekimoto G, Yoshida K, Uemura Y, Seki T, Taketani S, Fujisawa J, Okazaki K (2009) Smad2 and Smad3 phosphorylated at both linker and COOH-terminal regions transmit malignant TGF-β signal in later stages of human colorectal cancer. Cancer Res 69:5321-5330
75. Michalopoulos GK (2007) Liver regeneration. J Cell Physiol 213:286-300
76. Millet C, Yamashita M, Heller M, Yu LR, Veenstra TD, Zhang YE (2009) A negative feedback control of transforming growth factor-β signaling by glycogen synthase kinase 3-mediated Smad3 linker phosphorylation at Ser-204. J Biol Chem 284:19808-19816
77. Mori S, Matsuzaki K, Yoshida K, Furukawa F, Tahashi Y, Yamagata H, Sekimoto G, Seki T, Matsui H, Nishizawa M, Fujisawa J, Okazaki K (2004) TGF-β and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions. Oncogene 23:7416-7429 (Pubitemid 39382144)
78. Moses HL, Yang EY, Pietenpol JA (1990) TGF-β stimulation and inhibition of cell proliferation: new mechanistic insights. Cell 63:245-247
79. Murata M, Matsuzaki K, Yoshida K, Sekimoto G, Tahashi Y, Mori S, Uemura Y, Sakaida N, Fujisawa J, Seki T, Kobayashi K, Yokote K, KoikeK,Okazaki K(2009) Hepatitis B virusXprotein shifts human hepatic TGF-β signaling from tumor-suppression to oncogenesis in early chronic hepatitis B. Hepatology 49:1203-1217
80. Nagamine Y (2008) Transcriptional regulation of the plasminogen activator inhibitor type 1-with an emphasis on negative regulation. Thromb Haemost 100:1007-1013
81. Nagata H, Hatano E, Tada M, Murata M, Kitamura K, Asechi H, NaritaM, Yanagida A, Tamaki N, Yagi S, Ikai I, Matsuzaki K, Uemoto S (2009) Inhibition of c-Jun NH2-terminal kinase switches Smad3 signaling from oncogenesis to tumor-suppression in rat hepatocellular carcinoma. Hepatology 49:1944-1953
82. Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E (1996) TGF-β1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 10:2462-2477 (Pubitemid 26341881)
83. Oft M, Akhurst RJ, Balmain A (2002) Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol 4:487-494 (Pubitemid 34752433)
84. Omata M, Yoshida H (2004) Prevention and treatment of hepatocellular carcinoma. Liver Transpl 10:S111-S114 (Pubitemid 38240110)
85. Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, Witek RP, Alpini G, Venter J, Vandongen HM, Syn WK, Baroni GS, Benedetti A, Schuppan D, Diehl AM (2008) Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 118:3331-3342
86. Pardali K, Moustakas A (2007) Actions of TGF-β as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 1775:21-62 (Pubitemid 44881193)
87. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y (2004) NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461-466 (Pubitemid 39329586)
88. Pinzani M, Macias-Barragan J (2010) Update on the pathophysiology of liver fibrosis. Expert Rev Gastroenterol Hepatol 4:459-472
89. Popov Y, Schuppan D (2009) Targeting liver fibrosis: strategies for development and validation of antifibrotic therapies. Hepatology 50:1294-1306
90. Popov Y, Schuppan D (2010) Epithelial-to-mesenchymal transition in liver fibrosis: dead or alive? Gastroenterology 139:722-725
91. Rachakonda G, Sekhar KR, Jowhar D, Samson PC, Wikswo JP, Beauchamp RD, Datta PK, Freeman ML (2010) Increased cell migration and plasticity in Nrf2-deficient cancer cell lines. Oncogene 29:3703-3714
92. Ramadori G, Saile B (2004) Portal tract fibrogenesis in the liver. Lab Invest 84:153-159 (Pubitemid 41656496)
93. Reeves HL, Dack CL, Peak M, Burt AD, Day CP (2000) Stress-activated protein kinases in the activation of rat hepatic stellate cells in culture. J Hepatol 32:465-472 (Pubitemid 30136862)
94. Roberts AB, Sporn MB (1990) The transforming growth factor-βs. In: Sporn MB, Roberts AB (eds) Peptide growth factors and their receptors. Springer, Berlin, pp 419-472
95. Roberts AB, Tian F, Byfield SD, Stuelten C, Ooshima A, Saika S, Flanders KC (2006) Smad3 is key to TGF-β-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis. Cytokine Growth Factor Rev 17:19-27 (Pubitemid 43117513)
96. Roth-Eichhorn S, Kohl K, Gressner AM (1998) Subcellular localization of (latent) transforming growth factor β and the latent TGF-βbinding protein in rat hepatocytes and hepatic stellate cells. Hepatology 28:1588-1596 (Pubitemid 28549129)
97. Prokova V, Mavridou S, Papakosta P, Kardassis D (2005) Characterization of a novel transcriptionally active domain in the transforming growth factor β-regulated Smad3 protein. Nucleic Acids Res 33:3708-3721 (Pubitemid 41418540)
98. Saika S, Kono-Saika S, Ohnishi Y, Sato M, Muragaki Y, Ooshima A, Flanders KC, Yoo J, Anzano M, Liu CY, Kao WW, Roberts AB (2004) Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury. Am J Pathol 164:651-663 (Pubitemid 38364679)
99. Sapkota G, Knockaert M, Alarcón C, Montalvo E, Brivanlou AH, Massagué J (2006) Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-β pathways. J Biol Chem 281:40412-40419 (Pubitemid 46041844)
100. Sasseville M, Ritter LJ, Nguyen TM, Liu F, Mottershead DG, Russell DL, Gilchrist RB (2010) Growth differentiation factor 9 signaling requires ERK1/2 activity in mouse granulosa and cumulus cells. J Cell Sci 123:3166-3176
101. Schnabl B, Kweon YO, Frederick JP, Wang XF, Rippe RA, Brenner DA (2001) The role of Smad3 in mediating mouse hepatic stellate cell activation. Hepatology 34:89-100 (Pubitemid 32591487)
102. Scholten D, Osterreicher CH, Scholten A, Iwaisako K, Gu G, Brenner DA, Kisseleva T (2010) Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice. Gastroenterology 139:987-998
103. Sekimoto G, Matsuzaki K, Yoshida K, Mori S, MurataM, Seki T, Matsui H, Fujisawa J, Okazaki K (2007) Reversible Smad-dependent signaling between tumor suppression and oncogenesis. Cancer Res 67:5090-5096 (Pubitemid 46997243)
104. Shi Y, Massagué J (2003) Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113:685-700 (Pubitemid 36724933)
105. Shim JH, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS, Lee KY, Bussey C, Steckel M, Tanaka N, Yamada G, Akira S, Matsumoto K, Ghosh S (2005) TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev 19:2668-2681 (Pubitemid 41627934)
106. Shirai Y, Kawata S, Tamura S, Ito N, Tsushima H, Takaishi K et al (1994) Plasma transforming growth factor-β1 in patients with hepatocellular carcinoma: comparison with chronic liver diseases. Cancer 73:2275-2279 (Pubitemid 24129108)
107. Shiratori Y, Imazeki F, Moriyama M, Yano M, Arakawa Y, Yokosuka O, Kuroki T, Nishiguchi S, Sata M, Yamada G, Fujiyama S, Yoshida H, Omata M (2000) Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 132:517-524 (Pubitemid 30171890)
108. Sugano Y, Matsuzaki K, Tahashi Y, Furukawa F, Mori S, Yamagata H, Yoshida K, Matsushita M, Nishizawa M, Fujisawa J, Inoue K (2003) Distortion of autocrine transforming growth factor βsignal accelerates malignant potential by enhancing cell growth as well as PAI-1 and VEGF production in human hepatocellular carcinoma cells. Oncogene 22:2309-2321 (Pubitemid 36566786)
109. Suzuki K, Wilkes MC, Garamszegi N, Edens M, Leof EB (2007) Transforming growth factor β signaling via Ras in mesenchymal cells requires p21-activated kinase 2 for extracellular signal-regulated kinase-dependent transcriptional responses. Cancer Res 67:3673-3682 (Pubitemid 46762152)
110. 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-β signal in hepatic stellate cells between acute and chronic rat liver injury. Hepatology 35:49-61 (Pubitemid 34032543)
111. Taub R (2004) Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 5:836-847
112. Thorgeirsson SS, Grisham JW (2002) Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31:339-346 (Pubitemid 35154440)
113. Taura K, Miura K, Iwaisako K, Osterreicher CH, Kodama Y, Penz-Osterreicher M, Brenner DA (2010) Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology 51:1027-1036
114. Tilg H, Kaser A, Moschen AR (2006) How to modulate inflammatory cytokines in liver diseases. Liver Int 26:1029-1039 (Pubitemid 44541743)
115. Tremain R, Marko M, Kinnimulki V, Ueno H, Bottinger E, Glick A (2000) Defects in TGF-β signaling overcome senescence of mouse keratinocytes expressing v-Ha-ras. Oncogene 19:1698-1709 (Pubitemid 30200972)
116. Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, Nakanishi K, Fujimoto I, Inoue A, Yamazaki H, Kawashima T (1993) Risk factor for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 328:1797-1801 (Pubitemid 23174709)
117. Vasilaki E, Siderakis M, Papakosta P, Skourti-Stathaki K, Mavridou S, Kardassis D (2009) Novel regulation of Smad3 oligomerization and DNA binding by its linker domain. Biochemistry 48:8366-8378
118. Velden JL van der, Alcorn JF, Guala AS, Badura EC, Janssen-Heininger YM (2011) c-Jun N-terminal kinase 1 promotes transforming growth factor-{beta}1-induced epithelial-to-mesenchymal transition via control of linker phosphorylation and transcriptional activity of Smad3. Am J Respir Cell Mol Biol 44:571-581
119. Wakefield LM, Roberts AB (2002) TGF-β signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 12:22-29 (Pubitemid 34094985)
120. Wang G, Long J, Matsuura I, He D, Liu F (2005) The Smad3 linker region contains a transcriptional activation domain. Biochem J 386:29-34 (Pubitemid 40289221)
121. Wang G, Matsuura I, He D, Liu F (2009) Transforming growth factor-β-inducible phosphorylation of Smad3. J Biol Chem 284:9663-9673
122. Weinberg RA (2007) The biology of cancer. Garlang Science, New York
123. Weng HL, Ciuclan L, Liu Y, Hamzavi J, Godoy P, Gaitantzi H, Kanzler S, Heuchel R,UeberhamU, Gebhardt R, BreitkopfK, Dooley S (2007) Profibrogenic transforming growth factor-β/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes. Hepatology 46:1257-1270 (Pubitemid 350144790)
124. Wicks SJ, Lui S, Abdel-Wahab N, Mason RM, Chantry A (2000) Inactivation of Smad-transforming growth factor β signaling by Ca(2+)-calmodulin- dependent protein kinase II. Mol Cell Biol 20:8103-8111
125. Wrana JL (2000) Regulation of Smad activity. Cell 100:189-192
126. Wrighton KH, Lin X, Feng X-H (2009) Phospho-control of TGF-βsuperfamily signaling. Cell Res 19:8-20
127. Xu J, Lamouille S, Derynck R (2009) TGF-β-induced epithelial to mesenchymal transition. Cell Res 19:156-172
128. Yamada Y, Kirillova I, Peschon JJ, Fausto N (1997) Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci USA 94:1441-1446 (Pubitemid 27087870)
129. Yamagata H, Matsuzaki K, Mori S, Yoshida K, Tahashi Y, Furukawa F, Sekimoto G, Watanabe T, Uemura Y, Sakaida N, Yoshioka K, Kamiyama Y, Seki T, Okazaki K (2005) Acceleration of Smad2 and Smad3 phosphorylation via c-Jun NH(2)-terminal kinase during human colorectal carcinogenesis. Cancer Res 65:157-165 (Pubitemid 40070806)
130. Yang H, Kyo S, Takatura M, Sun L (2001) Autocrine transforming growth factor β suppresses telomerase activity and transcription of human telomerase reverse transcriptase in human cancer cells. Cell Growth Differ 12:119-127 (Pubitemid 32194901)
131. Yang Y, Yang S, Chen M, Zhang X, Zou Y, Zhang X (2008) Compound Astragalus and Salvia miltiorrhiza extract exerts antifibrosis by mediating TGF-β/Smad signaling in myofibroblasts. J Ethnopharmacol 118:264-270
132. Yang YA, Zhang GM, Feigenbaum L, Zhang YE (2006) Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2. Cancer Cell 9:445-457 (Pubitemid 43832193)
133. Yasuda H, Mine T, Shibata H, Eto Y, Hasegawa Y, Takeuchi T, Asano S, Kojima I (1993) Activin A: an autocrine inhibitor of initiation of DNA synthesis in rat hepatocytes. J Clin Invest 92:1491-1496 (Pubitemid 23273929)
134. Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, Inoue O, Yano M, Tanaka M, Fujiyama S, Nishiguchi S, Kuroki T, Imazeki F, Yokosuka O, Kinoyama S, Yamada G, Omata M (1999) Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of hepatocarcinogenesis by interferon therapy. Ann Intern Med 131:174-181 (Pubitemid 29364999)
135. Yoshida K, Matsuzaki K, Mori S, Tahashi Y, Yamagata H, Furukawa F, Seki T, Nishizawa M, Fujisawa J, Okazaki K (2005) Transforming growth factor-β 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 166:1029-1039 (Pubitemid 40524428)
136. Yue J, Mulder KM (2000) Requirement of Ras/MAPK pathway activation by transforming growth factor β for transforming growth factor β1 production in a Smad-dependent pathway. J Biol Chem 275:30765-30773
137. Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, Kalluri R (2007) Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 282:23337-23347 (Pubitemid 47311952)
138. Zhang JY, Tao S, Kimmel R, Khavari PA (2005) CDK4 regulation by TNFR1 and JNK is required for NF-κB-mediated epidermal growth control. J Cell Biol 168:561-566 (Pubitemid 40271021)
139. Zhang JY, Adams AE, Ridky TW, Tao S, Khavari PA (2007) Tumor necrosis factor receptor 1/c-Jun-NH2-kinase signaling promotes human neoplasia. Cancer Res 67:3827-3834 (Pubitemid 46762170)