KEGG   PATHWAY: ko05161Help
Entry
ko05161                     Pathway                                

Name
Hepatitis B
Description
Hepatitis B virus (HBV) is an enveloped virus and contains a partially double-stranded relaxed circular DNA (RC-DNA) genome. After entry into hepatocytes, HBV RC-DNA is transported to the nucleus and converted into a covalently closed circular molecule cccDNA. The cccDNA is the template for transcription of all viral RNAs including the pregenomic RNA (pgRNA), encoding for 7 viral proteins: large, middle, and small envelope proteins (LHBs, MHBs, and SHBs) that form the surface antigen (HBsAg), the core antigen (HBcAg), the e antigen (HBeAg), the HBV polymerase, and the regulatory protein X (HBx). The pgRNA interacts with the viral polymerase protein to initiate the encapsidation into the core particles. Through endoplasmic reticulum, the core particles finish assembling with the envelope proteins and are released. HBV infection leads to a wide spectrum of liver diseases raging from chronic hepatitis, cirrhosis to hepatocellular carcinoma. The mechanism of liver injury is still not clear. However, HBV proteins target host proteins, involved in a variety of functions, thus regulating transcription, cellular signaling cascades, proliferation, differentiation, and apoptosis.
Class
09160 Human Diseases; 09167 Infectious diseases
BRITE hierarchy
Pathway map
ko05161  Hepatitis B
ko05161

Ortholog table
Disease
H00048  Hepatocellular carcinoma
Orthology
K06255  heparan sulfate proteoglycan 2 (perlecan)
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K13375  transforming growth factor beta-1
K13376  transforming growth factor beta-2
K13377  transforming growth factor beta-3
K04674  TGF-beta receptor type-1 [EC:2.7.11.30]
K06625  cyclin-dependent kinase inhibitor 1A
K04377  Myc proto-oncogene protein
K12496  early growth response protein 2
K12497  early growth response protein 3
K04498  E1A/CREB-binding protein [EC:2.3.1.48]
K04389  tumor necrosis factor ligand superfamily member 6
K04390  tumor necrosis factor receptor superfamily member 6
K02373  FAS-associated death domain protein
K04398  caspase 8 [EC:3.4.22.61]
K04400  caspase 10 [EC:3.4.22.63]
K10610  DNA damage-binding protein 1
K10140  DNA damage-binding protein 2
K04416  mitogen-activated protein kinase kinase kinase 1 [EC:2.7.11.25]
K16197  14-3-3 protein beta/theta/zeta
K04430  mitogen-activated protein kinase kinase 4 [EC:2.7.12.2]
K04734  NF-kappa-B inhibitor alpha
K02580  nuclear factor NF-kappa-B p105 subunit
K04735  transcription factor p65
K01403  matrix metalloproteinase-9 (gelatinase B) [EC:3.4.24.35]
K02161  apoptosis regulator Bcl-2
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04456  RAC serine/threonine-protein kinase [EC:2.7.11.1]
K04467  inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10]
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]
K07210  inhibitor of nuclear factor kappa-B kinase subunit gamma
K02158  Bcl-2-antagonist of cell death
K04451  tumor protein p53
K01110  phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:3.1.3.67 3.1.3.48 3.1.3.16]
K04741  caspase 12 [EC:3.4.22.-]
K02084  apoptotic protease-activating factor
K16344  ragulator complex protein LAMTOR5
K08731  baculoviral IAP repeat-containing protein 5
K02159  apoptosis regulator BAX
K08738  cytochrome c
K04399  caspase 9 [EC:3.4.22.62]
K02187  caspase 3 [EC:3.4.22.56]
K15041  voltage-dependent anion channel protein 3
K04446  nuclear factor of activated T-cells, cytoplasmic 1
K17332  nuclear factor of activated T-cells, cytoplasmic 2
K17333  nuclear factor of activated T-cells, cytoplasmic 3
K17334  nuclear factor of activated T-cells, cytoplasmic 4
K03156  tumor necrosis factor superfamily, member 2
K05871  focal adhesion kinase 2 [EC:2.7.10.2]
K05704  tyrosine-protein kinase Src [EC:2.7.10.2]
K04364  growth factor receptor-binding protein 2
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K04448  transcription factor AP-1
K04501  mothers against decapentaplegic homolog 4
K04450  cyclic AMP-dependent transcription factor ATF-2
K10030  interleukin 8
K04802  proliferating cell nuclear antigen
K11217  Janus kinase 1 [EC:2.7.10.2]
K11220  signal transducer and activator of transcription 1
K11221  signal transducer and activator of transcription 2
K04692  signal transducer and activator of transcription 3
K11222  signal transducer and activator of transcription 4
K11223  signal transducer and activator of transcription 5A
K11224  signal transducer and activator of transcription 5B
K11225  signal transducer and activator of transcription 6
K03662  V-type H+-transporting ATPase S1 subunit
K02677  classical protein kinase C alpha type [EC:2.7.11.13]
K19662  classical protein kinase C beta type [EC:2.7.11.13]
K19663  classical protein kinase C gamma type [EC:2.7.11.13]
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K05870  cyclic AMP-responsive element-binding protein 1
K09048  cyclic AMP-responsive element-binding protein 3
K04374  cyclic AMP-dependent transcription factor ATF-4
K09047  cyclic AMP-responsive element-binding protein 5
K09049  cyclic AMP-dependent transcription factor ATF-6 beta
K04379  proto-oncogene protein c-fos
K04375  ETS domain-containing protein Elk-1
K11594  ATP-dependent RNA helicase DDX3X [EC:3.6.4.13]
K05414  interferon alpha
K05130  interferon receptor 1
K05401  toll-like receptor 3
K05842  toll-like receptor adapter molecule 1
K12646  ATP-dependent RNA helicase DDX58 [EC:3.6.3.14]
K12647  interferon-induced helicase C domain-containing protein 1 [EC:3.6.4.13]
K12648  mitochondrial antiviral-signaling protein
K07211  inhibitor of nuclear factor kappa-B kinase subunit epsilon [EC:2.7.11.10]
K05410  TANK-binding kinase 1 [EC:2.7.11.10]
K05411  interferon regulatory factor 3
K09447  interferon regulatory factor 7
K10160  toll-like receptor 4
K05409  TRIF-related adaptor molecule
K05415  interferon beta
K10159  toll-like receptor 2
K05403  toll-interleukin 1 receptor (TIR) domain-containing adaptor protein
K04729  myeloid differentiation primary response protein MyD88
K05405  interleukin 6
K04503  G1/S-specific cyclin-D1
K02089  cyclin-dependent kinase 4 [EC:2.7.11.22]
K02091  cyclin-dependent kinase 6 [EC:2.7.11.22]
K06618  retinoblastoma-associated protein
K17454  transcription factor E2F1
K09389  transcription factor E2F2
K06620  transcription factor E2F3
K06624  cyclin-dependent kinase inhibitor 1B
K06626  G1/S-specific cyclin-E1
K02206  cyclin-dependent kinase 2 [EC:2.7.11.22]
K06627  cyclin-A
Reference
  Authors
Schadler S, Hildt E
  Title
HBV life cycle: entry and morphogenesis.
  Journal
Viruses 1:185-209 (2009)
DOI:10.3390/v1020185
Reference
  Authors
Schulze A, Gripon P, Urban S
  Title
Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans.
  Journal
Hepatology 46:1759-68 (2007)
DOI:10.1002/hep.21896
Reference
  Authors
Ng SA, Lee C
  Title
Hepatitis B virus X gene and hepatocarcinogenesis.
  Journal
J Gastroenterol 46:974-90 (2011)
DOI:10.1007/s00535-011-0415-9
Reference
  Authors
Murata M, Matsuzaki K, Yoshida K, Sekimoto G, Tahashi Y, Mori S, Uemura Y, Sakaida N, Fujisawa J, Seki T, Kobayashi K, Yokote K, Koike K, Okazaki K
  Title
Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)-beta signaling from tumor suppression to oncogenesis in early chronic hepatitis B.
  Journal
Hepatology 49:1203-17 (2009)
DOI:10.1002/hep.22765
Reference
PMID:8764004
  Authors
Benn J, Su F, Doria M, Schneider RJ
  Title
Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases.
  Journal
J Virol 70:4978-85 (1996)
Reference
  Authors
Bouchard MJ, Schneider RJ
  Title
The enigmatic X gene of hepatitis B virus.
  Journal
J Virol 78:12725-34 (2004)
DOI:10.1128/JVI.78.23.12725-12734.2004
Reference
  Authors
Park NH, Song IH, Chung YH
  Title
Chronic hepatitis B in hepatocarcinogenesis.
  Journal
Postgrad Med J 82:507-15 (2006)
DOI:10.1136/pgmj.2006.047431
Reference
  Authors
Kwun HJ, Jang KL
  Title
Natural variants of hepatitis B virus X protein have differential effects on the expression of cyclin-dependent kinase inhibitor p21 gene.
  Journal
Nucleic Acids Res 32:2202-13 (2004)
DOI:10.1093/nar/gkh553
Reference
  Authors
Yoo YG, Lee MO
  Title
Hepatitis B virus X protein induces expression of Fas ligand gene through enhancing transcriptional activity of early growth response factor.
  Journal
J Biol Chem 279:36242-9 (2004)
DOI:10.1074/jbc.M401290200
Reference
  Authors
Cougot D, Wu Y, Cairo S, Caramel J, Renard CA, Levy L, Buendia MA, Neuveut C
  Title
The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription.
  Journal
J Biol Chem 282:4277-87 (2007)
DOI:10.1074/jbc.M606774200
Reference
  Authors
Kim SY, Kim JK, Kim HJ, Ahn JK
  Title
Hepatitis B virus X protein sensitizes UV-induced apoptosis by transcriptional transactivation of Fas ligand gene expression.
  Journal
IUBMB Life 57:651-8 (2005)
DOI:10.1080/15216540500239697
Reference
PMID:9325306
  Authors
Rehemtulla A, Hamilton CA, Chinnaiyan AM, Dixit VM
  Title
Ultraviolet radiation-induced apoptosis is mediated by activation of CD-95 (Fas/APO-1).
  Journal
J Biol Chem 272:25783-6 (1997)
DOI:10.1074/jbc.272.41.25783
Reference
  Authors
Zhang X, Zhang H, Ye L
  Title
Effects of hepatitis B virus X protein on the development of liver cancer.
  Journal
J Lab Clin Med 147:58-66 (2006)
DOI:10.1016/j.lab.2005.10.003
Reference
  Authors
Diao J, Khine AA, Sarangi F, Hsu E, Iorio C, Tibbles LA, Woodgett JR, Penninger J, Richardson CD
  Title
X protein of hepatitis B virus inhibits Fas-mediated apoptosis and is associated with up-regulation of the SAPK/JNK pathway.
  Journal
J Biol Chem 276:8328-40 (2001)
DOI:10.1074/jbc.M006026200
Reference
  Authors
Sun B, Karin M
  Title
NF-kappaB signaling, liver disease and hepatoprotective agents.
  Journal
Oncogene 27:6228-44 (2008)
DOI:10.1038/onc.2008.300
Reference
  Authors
Weil R, Sirma H, Giannini C, Kremsdorf D, Bessia C, Dargemont C, Brechot C, Israel A
  Title
Direct association and nuclear import of the hepatitis B virus X protein with the NF-kappaB inhibitor IkappaBalpha.
  Journal
Mol Cell Biol 19:6345-54 (1999)
DOI:10.1128/MCB.19.9.6345
Reference
  Authors
Um HR, Lim WC, Chae SY, Park S, Park JH, Cho H
  Title
Raf-1 and protein kinase B regulate cell survival through the activation of NF-kappaB in hepatitis B virus X-expressing cells.
  Journal
Virus Res 125:1-8 (2007)
DOI:10.1016/j.virusres.2006.11.007
Reference
  Authors
Chung TW, Lee YC, Kim CH
  Title
Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential.
  Journal
FASEB J 18:1123-5 (2004)
DOI:10.1096/fj.03-1429fje
Reference
  Authors
Kim HJ, Kim SY, Kim J, Lee H, Choi M, Kim JK, Ahn JK
  Title
Hepatitis B virus X protein induces apoptosis by enhancing translocation of Bax to mitochondria.
  Journal
IUBMB Life 60:473-80 (2008)
DOI:10.1002/iub.68
Reference
  Authors
Terradillos O, de La Coste A, Pollicino T, Neuveut C, Sitterlin D, Lecoeur H, Gougeon ML, Kahn A, Buendia MA
  Title
The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver.
  Journal
Oncogene 21:377-86 (2002)
DOI:10.1038/sj.onc.1205110
Reference
  Authors
Lee YI, Kang-Park S, Do SI, Lee YI
  Title
The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade.
  Journal
J Biol Chem 276:16969-77 (2001)
DOI:10.1074/jbc.M011263200
Reference
  Authors
Huang WC, Chen WS, Chen YJ, Wang LY, Hsu SC, Chen CC, Hung MC
  Title
Hepatitis B virus X protein induces IKKalpha nuclear translocation via Akt-dependent phosphorylation to promote the motility of hepatocarcinoma cells.
  Journal
J Cell Physiol 227:1446-54 (2012)
DOI:10.1002/jcp.22860
Reference
  Authors
Chung TW, Lee YC, Ko JH, Kim CH
  Title
Hepatitis B Virus X protein modulates the expression of PTEN by inhibiting the function of p53, a transcriptional activator in liver cells.
  Journal
Cancer Res 63:3453-8 (2003)
Reference
  Authors
Matsuda Y, Ichida T
  Title
Impact of hepatitis B virus X protein on the DNA damage response during hepatocarcinogenesis.
  Journal
Med Mol Morphol 42:138-42 (2009)
DOI:10.1007/s00795-009-0457-8
Reference
  Authors
Benhenda S, Cougot D, Buendia MA, Neuveut C
  Title
Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis.
  Journal
Adv Cancer Res 103:75-109 (2009)
DOI:10.1016/S0065-230X(09)03004-8
Reference
PMID:9843511
  Authors
Lara-Pezzi E, Armesilla AL, Majano PL, Redondo JM, Lopez-Cabrera M
  Title
The hepatitis B virus X protein activates nuclear factor of activated T cells (NF-AT) by a cyclosporin A-sensitive pathway.
  Journal
EMBO J 17:7066-77 (1998)
DOI:10.1093/emboj/17.23.7066
Reference
  Authors
Gurtsevitch VE
  Title
Human oncogenic viruses: hepatitis B and hepatitis C viruses and their role in hepatocarcinogenesis.
  Journal
Biochemistry (Mosc) 73:504-13 (2008)
DOI:10.1134/S0006297908050039
Reference
PMID:9738022
  Authors
Lee YH, Yun Y
  Title
HBx protein of hepatitis B virus activates Jak1-STAT signaling.
  Journal
J Biol Chem 273:25510-5 (1998)
DOI:10.1074/jbc.273.39.25510
Reference
  Authors
Waris G, Huh KW, Siddiqui A
  Title
Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-kappa B via oxidative stress.
  Journal
Mol Cell Biol 21:7721-30 (2001)
DOI:10.1128/MCB.21.22.7721-7730.2001
Reference
  Authors
Diao J, Garces R, Richardson CD
  Title
X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis.
  Journal
Cytokine Growth Factor Rev 12:189-205 (2001)
DOI:10.1016/S1359-6101(00)00034-4
Reference
  Authors
Mayr B, Montminy M
  Title
Transcriptional regulation by the phosphorylation-dependent factor CREB.
  Journal
Nat Rev Mol Cell Biol 2:599-609 (2001)
DOI:10.1038/35085068
Reference
  Authors
Dandri M, Locarnini S
  Title
New insight in the pathobiology of hepatitis B virus infection.
  Journal
Gut 61 Suppl 1:i6-17 (2012)
DOI:10.1136/gutjnl-2012-302056
Reference
  Authors
Lang T, Lo C, Skinner N, Locarnini S, Visvanathan K, Mansell A
  Title
The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway.
  Journal
J Hepatol 55:762-9 (2011)
DOI:10.1016/j.jhep.2010.12.042
Reference
  Authors
Wang H, Ryu WS
  Title
Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: implications for immune evasion.
  Journal
PLoS Pathog 6:e1000986 (2010)
DOI:10.1371/journal.ppat.1000986
Reference
  Authors
Wu M, Xu Y, Lin S, Zhang X, Xiang L, Yuan Z
  Title
Hepatitis B virus polymerase inhibits the interferon-inducible MyD88 promoter by blocking nuclear translocation of Stat1.
  Journal
J Gen Virol 88:3260-9 (2007)
DOI:10.1099/vir.0.82959-0
Reference
  Authors
Klein A, Guhl E, Tzeng YJ, Fuhrhop J, Levrero M, Graessmann M, Graessmann A
  Title
HBX causes cyclin D1 overexpression and development of breast cancer in transgenic animals that are heterozygous for p53.
  Journal
Oncogene 22:2910-9 (2003)
DOI:10.1038/sj.onc.1206539
Reference
  Authors
Bouchard M, Giannakopoulos S, Wang EH, Tanese N, Schneider RJ
  Title
Hepatitis B virus HBx protein activation of cyclin A-cyclin-dependent kinase 2 complexes and G1 transit via a Src kinase pathway.
  Journal
J Virol 75:4247-57 (2001)
DOI:10.1128/JVI.75.9.4247-4257.2001
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