JNKs in liver diseases

  • R. SchwabeEmail author


c-Jun NH2-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family. Like other MAPKs, JNKs are conserved throughout eukaryotic evolution, activated via three-tiered phosphorylation cascades, and involved in a wide range of cellular responses to stress. JNKs have been shown to play important roles in proliferation, cell death, inflammation and cell metabolism. These seemingly unrelated responses are part of an overall stress response program that ensures proper repair of cells sustaining minor damage, elimination of cells sustaining irreversible structural or genetic damage, as well as their proper replacement.


Liver Injury Liver Regeneration Hepatic Stellate Cell Hepatocyte Cell Death Hepatic Reperfusion Injury 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by NIH grants R01DK076920 and U54CA126513.


  1.  1.
    Gupta S, Barrett T, Whitmarsh AJ et al (1996) Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J 15:2760–2770PubMedGoogle Scholar
  2.  2.
    Hibi M, Lin A, Smeal T et al (1993) Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev 7: 2135–2148CrossRefPubMedGoogle Scholar
  3.  3.
    Mohit AA, Martin JH, Miller CA (1995) p493F12 kinase: a novel MAP kinase expressed in a subset of neurons in the human nervous system. Neuron 14:67–78CrossRefPubMedGoogle Scholar
  4.  4.
    Kuan CY, Yang DD, Samanta Roy DR et al (1999) The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron 22:667–676CrossRefPubMedGoogle Scholar
  5.  5.
    Sabapathy K, Jochum W, Hochedlinger K et al (1999) Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2. Mech Dev 89: 115–124CrossRefPubMedGoogle Scholar
  6.  6.
    Sato S, Sanjo H, Tsujimura T et al (2006) TAK1 is indispensable for development of T cells and prevention of colitis by the generation of regulatory T cells. Int Immunol 18: 1405–1411CrossRefPubMedGoogle Scholar
  7.  7.
    Shim JH, Xiao C, Paschal AE et al (2005) TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev 19:2668–2681CrossRefPubMedGoogle Scholar
  8.  8.
    Wan YY, Chi H, Xie M et al (2006) The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function. Nat Immunol 7:851–858CrossRefPubMedGoogle Scholar
  9.  9.
    Tobiume K, Matsuzawa A, Takahashi T et al (2001) ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep 2:222–228CrossRefPubMedGoogle Scholar
  10. 10.
    Nishitoh H, Matsuzawa A, Tobiume K et al (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 16:1345–1355CrossRefPubMedGoogle Scholar
  11. 11.
    Saitoh M, Nishitoh H, Fujii M et al (1998) Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J 17:2596–2606CrossRefPubMedGoogle Scholar
  12. 12.
    Tournier C, Dong C, Turner TK et al (2001) MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes Dev 15:1419–1426CrossRefPubMedGoogle Scholar
  13. 13.
    Liu Y, Shepherd EG, Nelin LD (2007) MAPK phosphatases–regulating the immune response. Nat Rev Immunol 7: 202–212CrossRefPubMedGoogle Scholar
  14. 14.
    Kamata H, Honda S, Maeda S et al (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120:649–661CrossRefPubMedGoogle Scholar
  15. 15.
    Hamdi M, Kool J, Cornelissen-Steijger P et al (2005) DNA damage in transcribed genes induces apoptosis via the JNK pathway and the JNK-phosphatase MKP-1. Oncogene 24:7135–7144CrossRefPubMedGoogle Scholar
  16. 16.
    Heinrichsdorff J, Luedde T, Perdiguero E, Nebreda AR, Pasparakis M. (2008) p38 alpha MAPK inhibits JNK activation and collaborates with IkappaB kinase 2 to prevent endotoxin-induced liver failure. EMBO Rep 9:1048-54 Google Scholar
  17. 17.
    Hui L, Bakiri L, Mairhorfer A et al (2007) p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat Genet 39:741–749CrossRefPubMedGoogle Scholar
  18. 18.
    Sakurai T, He G, Matsuzawa A et al (2008) Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14:156–165CrossRefPubMedGoogle Scholar
  19. 19.
    Mechta-Grigoriou F, Gerald D, Yaniv M (2001) The mammalian Jun proteins: redundancy and specificity. Oncogene 20:2378–2389CrossRefPubMedGoogle Scholar
  20. 20.
    Smeal T, Binetruy B, Mercola DA et al (1991) Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature 354: 494–496CrossRefPubMedGoogle Scholar
  21. 21.
    Angel P, Hattori K, Smeal T et al (1988) The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell 55:875–885CrossRefPubMedGoogle Scholar
  22. 22.
    Minden A, Karin M (1997) Regulation and function of the JNK subgroup of MAP kinases. Biochim Biophys Acta 1333:F85–F104Google Scholar
  23. 23.
    Bogoyevitch MA, Kobe B (2006) Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases. Microbiol Mol Biol Rev 70:1061–1095CrossRefPubMedGoogle Scholar
  24. 24.
    Sabapathy K, Hochedlinger K, Nam SY et al (2004) Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Mol Cell 15:713–725CrossRefPubMedGoogle Scholar
  25. 25.
    Jaeschke A, Karasarides M, Ventura JJ et al (2006) JNK2 is a positive regulator of the cJun transcription factor. Mol Cell 23:899–911CrossRefPubMedGoogle Scholar
  26. 26.
    Gao M, Labuda T, Xia Y et al (2004) Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 306:271–275CrossRefPubMedGoogle Scholar
  27. 27.
    Chang L, Kamata H, Solinas G et al (2006) The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell 124:601–613CrossRefPubMedGoogle Scholar
  28. 28.
    Chen N, She QB, Bode AM et al (2002) Differential gene expression profiles of Jnk1- and Jnk2-deficient murine fibroblast cells. Cancer Res 62:1300–1304PubMedGoogle Scholar
  29. 29.
    Varfolomeev EE, Ashkenazi A (2004) Tumor necrosis factor: an apoptosis JuNKie? Cell 116:491–497CrossRefPubMedGoogle Scholar
  30. 30.
    Ventura JJ, Hubner A, Zhang C et al (2006) Chemical genetic analysis of the time course of signal transduction by JNK. Mol Cell 21:701–710CrossRefPubMedGoogle Scholar
  31. 31.
    Lamb JA, Ventura JJ, Hess P et al (2003) JunD mediates survival signaling by the JNK signal transduction pathway. Mol Cell 11:1479–1489CrossRefPubMedGoogle Scholar
  32. 32.
    Hasselblatt P, Rath M, Komnenovic V et al (2007) Hepatocyte survival in acute hepatitis is due to c-Jun/AP-1-dependent expression of inducible nitric oxide synthase. Proc Natl Acad Sci U S A 104:17105–17110CrossRefPubMedGoogle Scholar
  33. 33.
    Deng X, Xiao L, Lang W et al (2001) Novel role for JNK as a stress-activated Bcl2 kinase. J Biol Chem 276: 23681–23688CrossRefPubMedGoogle Scholar
  34. 34.
    Tang F, Tang G, Xiang J et al (2002) The absence of NF-kappaB-mediated inhibition of c-Jun N-terminal kinase activation contributes to tumor necrosis factor alpha-induced apoptosis. Mol Cell Biol 22:8571–8579CrossRefPubMedGoogle Scholar
  35. 35.
    Tang G, Minemoto Y, Dibling B et al (2001) Inhibition of JNK activation through NF-kappaB target genes. Nature 414:313–317CrossRefPubMedGoogle Scholar
  36. 36.
    Inoshita S, Takeda K, Hatai T et al (2002) Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress. J Biol Chem 277:43730–43734CrossRefPubMedGoogle Scholar
  37. 37.
    Kharbanda S, Saxena S, Yoshida K et al (2000) Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage. J Biol Chem 275:322–327CrossRefPubMedGoogle Scholar
  38. 38.
    Tsuruta F, Sunayama J, Mori Y et al (2004) JNK promotes Bax translocation to mitochondria through phosphorylation of 14–3-3 proteins. EMBO J 23:1889–1899CrossRefPubMedGoogle Scholar
  39. 39.
    Deng Y, Ren X, Yang L et al (2003) A JNK-dependent pathway is required for TNFalpha-induced apoptosis. Cell 115:61–70CrossRefPubMedGoogle Scholar
  40. 40.
    Lu C, Zhu F, Cho YY et al (2006) Cell apoptosis: requirement of H2AX in DNA ladder formation, but not for the activation of caspase-3. Mol Cell 23:121–132CrossRefPubMedGoogle Scholar
  41. 41.
    Noguchi K, Kitanaka C, Yamana H et al (1999) Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase. J Biol Chem 274:32580–32587CrossRefPubMedGoogle Scholar
  42. 42.
    Schreiber M, Kolbus A, Piu F et al (1999) Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev 13:607–619CrossRefPubMedGoogle Scholar
  43. 43.
    Behrens A, Sibilia M, Wagner EF (1999) Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet 21:326–329CrossRefPubMedGoogle Scholar
  44. 44.
    Wagner EF, Eferl R (2005) Fos/AP-1 proteins in bone and the immune system. Immunol Rev 208:126–140CrossRefPubMedGoogle Scholar
  45. 45.
    Ishizuka T, Terada N, Gerwins P et al (1997) Mast cell tumor necrosis factor alpha production is regulated by MEK kinases. Proc Natl Acad Sci U S A 94:6358–6363CrossRefPubMedGoogle Scholar
  46. 46.
    Bennett BL, Sasaki DT, Murray BW et al (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A 98:13681–13686CrossRefPubMedGoogle Scholar
  47. 47.
    Han Z, Boyle DL, Chang L et al (2001) c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 108:73–81PubMedGoogle Scholar
  48. 48.
    Schwabe RF, Bataller R, Brenner DA (2003) Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. Am J Physiol Gastrointest Liver Physiol 285:G949–G958Google Scholar
  49. 49.
    Marra F, Delogu W, Petrai I et al (2004) Differential requirement of members of the MAPK family for CCL2 expression by hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 287:G18–G26CrossRefGoogle Scholar
  50. 50.
    Dong C, Yang DD, Tournier C et al (2000) JNK is required for effector T-cell function but not for T-cell activation. Nature 405:91–94CrossRefPubMedGoogle Scholar
  51. 51.
    Liu H, Lo CR, Czaja MJ (2002) NF-kappaB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun. Hepatology 35: 772–778CrossRefPubMedGoogle Scholar
  52. 52.
    Schwabe RF, Uchinami H, Qian T et al (2004) Differential requirement for c-Jun NH2-terminal kinase in TNFalpha- and Fas-mediated apoptosis in hepatocytes. FASEB J 18: 720–722PubMedGoogle Scholar
  53. 53.
    Henderson NC, Pollock KJ, Frew J et al (2007) Critical role of c-jun (NH2) terminal kinase in paracetamol-induced acute liver failure. Gut 56:982–990CrossRefPubMedGoogle Scholar
  54. 54.
    Maeda S, Chang L, Li ZW et al (2003) IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity 19:725–737CrossRefPubMedGoogle Scholar
  55. 55.
    Wang Y, Singh R, Lefkowitch JH et al (2006) Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. J Biol Chem 281:15258–15267CrossRefPubMedGoogle Scholar
  56. 56.
    Ni HM, Chen X, Ding WX et al (2008) Differential roles of JNK in ConA/GalN and ConA-induced liver injury in mice. Am J Pathol 173:962–972CrossRefPubMedGoogle Scholar
  57. 57.
    Das M, Sabio G, Jiang F et al (2009) Induction of hepatitis by JNK-mediated expression of TNF-alpha. Cell 136:249–260CrossRefPubMedGoogle Scholar
  58. 58.
    Lee WM (2003) Acute liver failure in the United States. Semin Liver Dis 23:217–226CrossRefPubMedGoogle Scholar
  59. 59.
    Jaeschke H, Bajt ML (2006) Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 89:31–41CrossRefPubMedGoogle Scholar
  60. 60.
    Gunawan BK, Liu ZX, Han D et al (2006) c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gastroenterology 131:165–178CrossRefPubMedGoogle Scholar
  61. 61.
    Nakagawa H, Maeda S, Hikiba Y et al (2008) Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-­induced liver injury by inhibiting c-Jun N-terminal kinase activation. Gastroenterology 135:1311–1321CrossRefPubMedGoogle Scholar
  62. 62.
    Hanawa N, Shinohara M, Saberi B et al (2008) Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem 283:13565–13577CrossRefPubMedGoogle Scholar
  63. 63.
    Kon K, Kim JS, Jaeschke H et al (2004) Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology 40: 1170–1179CrossRefPubMedGoogle Scholar
  64. 64.
    Beales D, McLean AE (1996) Protection in the late stages of paracetamol-induced liver cell injury with fructose, cyslosporin A and trifluoperazine. Toxicology 107:201–208CrossRefPubMedGoogle Scholar
  65. 65.
    Rudiger HA, Clavien PA (2002) Tumor necrosis factor alpha, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver. Gastroenterology 122:202–210CrossRefPubMedGoogle Scholar
  66. 66.
    Colletti LM, Remick DG, Burtch GD et al (1990) Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest 85:1936–1943CrossRefPubMedGoogle Scholar
  67. 67.
    Bradham CA, Stachlewitz RF, Gao W et al (1997) Reper­fusion after liver transplantation in rats differentially activates the mitogen-activated protein kinases. Hepatology 25: 1128–1135CrossRefPubMedGoogle Scholar
  68. 68.
    Zwacka RM, Zhang Y, Zhou W et al (1998) Ischemia/reperfusion injury in the liver of BALB/c mice activates AP-1 and nuclear factor kappaB independently of IkappaB degradation. Hepatology 28:1022–1030CrossRefPubMedGoogle Scholar
  69. 69.
    Lehmann TG, Wheeler MD, Schwabe RF et al (2000) Gene delivery of Cu/Zn-superoxide dismutase improves graft function after transplantation of fatty livers in the rat. Hepatology 32:1255–1264CrossRefPubMedGoogle Scholar
  70. 70.
    Uehara T, Bennett B, Sakata ST et al (2005) JNK mediates hepatic ischemia reperfusion injury. J Hepatol 42:850–859CrossRefPubMedGoogle Scholar
  71. 71.
    Uehara T, Xi Peng X, Bennett B et al (2004) c-Jun N-terminal kinase mediates hepatic injury after rat liver transplantation. Transplantation 78:324–332CrossRefPubMedGoogle Scholar
  72. 72.
    Theruvath TP, Snoddy MC, Zhong Z et al (2008) Mito­chondrial permeability transition in liver ischemia and reperfusion: role of c-Jun N-terminal kinase 2. Transplantation 85:1500–1504CrossRefPubMedGoogle Scholar
  73. 73.
    Yoshida K, Matsuzaki K, Mori S et al (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 166:1029–1039PubMedGoogle Scholar
  74. 74.
    Bataller R, Schwabe RF, Choi YH et al (2003) NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest 112: 1383–1394PubMedGoogle Scholar
  75. 75.
    Schnabl B, Bradham CA, Bennett BL et al (2001) TAK1/JNK and p38 have opposite effects on rat hepatic stellate cells. Hepatology 34:953–963CrossRefPubMedGoogle Scholar
  76. 76.
    Taub R (2004) Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 5:836–847CrossRefPubMedGoogle Scholar
  77. 77.
    Westwick JK, Weitzel C, Leffert HL et al (1995) Activation of Jun kinase is an early event in hepatic regeneration. J Clin Invest 95:803–810CrossRefPubMedGoogle Scholar
  78. 78.
    Schwabe RF, Bradham CA, Uehara T et al (2003) c-Jun-N-terminal kinase drives cyclin D1 expression and proliferation during liver regeneration. Hepatology 37:824–832CrossRefPubMedGoogle Scholar
  79. 79.
    Behrens A, Sibilia M, David JP et al (2002) Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-jun in the liver. EMBO J 21:1782–1790CrossRefPubMedGoogle Scholar
  80. 80.
    Hui L, Zatloukal K, Scheuch H et al (2008) Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J Clin Invest 118:3943–3953CrossRefPubMedGoogle Scholar
  81. 81.
    Sabapathy K, Wagner EF (2004) JNK2: a negative regulator of cellular proliferation. Cell Cycle 3:1520–1523PubMedGoogle Scholar
  82. 82.
    Papa S, Zazzeroni F, Fu YX et al (2008) Gadd45beta promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling. J Clin Invest 118: 1911–1923CrossRefPubMedGoogle Scholar
  83. 83.
    Bohmann D, Bos TJ, Admon A et al (1987) Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. Science 238:1386–1392CrossRefPubMedGoogle Scholar
  84. 84.
    Eferl R, Ricci R, Kenner L et al (2003) Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell 112:181–192CrossRefPubMedGoogle Scholar
  85. 85.
    Sakurai T, Maeda S, Chang L et al (2006) Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci U S A 103:10544–10551CrossRefPubMedGoogle Scholar
  86. 86.
    Maeda S, Kamata H, Luo JL et al (2005) IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121:977–990CrossRefPubMedGoogle Scholar
  87. 87.
    Li Z, Yang S, Lin H et al (2003) Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37:343–350CrossRefPubMedGoogle Scholar
  88. 88.
    Schattenberg JM, Singh R, Wang Y et al (2006) JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 43:163–172CrossRefPubMedGoogle Scholar
  89. 89.
    Singh R, Wang Y, Xiang Y et al (2009) Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology 49:87–96CrossRefPubMedGoogle Scholar
  90. 90.
    Kodama Y, Kisseleva T, Miura K et al (2008) JNK1 in hematopoietic cells mediates progression from diet-induced hepatic steatosis to steatohepatits and liver fibrosis. Hepa­tology 48:366AGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of Medicinecolumbia UniversityNew YorkUSA

Personalised recommendations