Skip to main content
Log in

Role of nuclear constitutive androstane receptor in regulation of hepatocyte proliferation and hepatocarcinogenesis

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Activation of the constitutive androstane receptor (CAR) in hepatocytes occurs as a body adaptation in response to a number of external influences, and its functional activity is primarily related to induction of enzymes detoxifying xenobiotics. However, special attention was recently given to CAR due to the fact that its key role becomes unveiled in various physiological and pathophysiological processes occurring in the liver: gluconeogenesis, metabolism of fatty acids and bilirubin, hormonal regulation, proliferation of hepatocytes, and hepatocarcinogenesis. Here we review the main pathways and mechanisms that elevate hepatocyte proliferative activity related to CAR and whose disturbance may be a pivotal factor in hepatocarcinogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Kachaylo, E. M., Pustylnyak, V. O., Lyakhovich, V. V., and Gulyaeva, L. F. (2011) Constitutive androstane receptor (CAR) is a xenosensor and target for therapy, Biochemistry (Moscow), 76, 1087–1097.

    Article  CAS  Google Scholar 

  2. Wei, P., Zhang, J., Egan-Hafley, M., Liang, S., and Moore, D. D. (2000) The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism, Nature, 407, 920–923.

    Article  CAS  PubMed  Google Scholar 

  3. Maglich, J. M., Stoltz, C. M., Goodwin, B., Hawkins Brown, D., Moore, J. T., and Kliewer, S. A. (2002) Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification, Mol. Pharmacol., 62, 638–646.

    Article  CAS  PubMed  Google Scholar 

  4. Xie, W., Barwick, J. L., Simon, C. M., Pierce, A. M., Safe, S., Blumberg, B., Guzelian, P. S., and Evans, R. M. (2000) Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR, Genes Dev., 14, 3014–3023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Costa, R. H., Kalinichenko, V. V., Tan, Y., and Wang, I. C. (2005) The CAR nuclear receptor and hepatocyte proliferation, Hepatology, 42, 1004–1008.

    Article  CAS  PubMed  Google Scholar 

  6. Yamamoto, Y., Moore, R., Goldsworthy, T. L., Negishi, M., and Maronpot, R. R. (2004) The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice, Cancer Res., 64, 7197–7200.

    Article  CAS  PubMed  Google Scholar 

  7. Kobayashi, K., Sueyoshi, T., Inoue, K., Moore, R., and Negishi, M. (2003) Cytoplasmic accumulation of the nuclear receptor CAR by a tetratricopeptide repeat protein in HepG2 cells, Mol. Pharmacol., 64, 1069–1075.

    Article  CAS  PubMed  Google Scholar 

  8. Yoshinari, K., Kobayashi, K., Moore, R., Kawamoto, T., and Negishi, M. (2003) Identification of the nuclear receptor CAR–HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital, FEBS Lett., 548, 17–20.

    Article  CAS  PubMed  Google Scholar 

  9. Suino, K., Peng, L., Reynolds, R., Li, Y., Cha, J. Y., Repa, J. J., Kliewer, S. A., and Xu, H. E. (2004) The nuclear xenobiotic receptor CAR: structural determinants of constitutive activation and heterodimerization, Mol. Cell, 16, 893–905.

    CAS  PubMed  Google Scholar 

  10. Bourguet, W., Germain, P., and Gronemeyer, H. (2000) Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications, Trends Pharmacol. Sci., 21, 381–388.

    Article  CAS  PubMed  Google Scholar 

  11. Bourguet, W., Ruff, M., Chambon, P., Gronemeyer, H., and Moras, D. (1995) Crystal structure of the ligand-binding domain of the human nuclear receptor RXRα, Nature (London), 375, 377–382.

    Article  CAS  Google Scholar 

  12. Xu, R. X., Lambert, M. H., Wisely, B. B., Warren, E. N., Weinert, E. E., Waitt, G. M., Williams, J. D., Collins, J. L., Moore, L. B., Willson, T. M., and Moore, J. T. (2004) A structural basis for constitutive activity in the human CAR/RXR heterodimer, Mol. Cell, 16, 919–928.

    Article  CAS  PubMed  Google Scholar 

  13. Dussault, I., Lin, M., Hollister, K., Fan, M., Termini, J., Sherman, M. A., and Forman, B. M. (2002) A structural model of the constitutive androstane receptor defines novel interactions that mediate ligand-independent activity, Mol. Cell. Biol., 22, 5270–5280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sakai, H., Iwata, H., Kim, E. Y., Tsydenova, O., Miyazaki, N., Petrov, E. A., Batoev, V. B., and Tanabe, S. (2006) Constitutive androstane receptor (CAR) as a potential sensing biomarker of persistent organic pollutants (POPs) in aquatic mammal: molecular characterization, expression level, and ligand profiling in Baikal seal (Pusa sibirica), Toxicol. Sci., 94, 57–70.

    Article  CAS  PubMed  Google Scholar 

  15. Huang, W., Zhang, J., Wei, P., Schrader, W. T., and Moore, D. D. (2004) Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR, Mol. Endocrinol., 18, 2402–2408.

    Article  CAS  PubMed  Google Scholar 

  16. Tzameli, I., Pissios, P., Schuetz, E. G., and Moore, D. D. (2000) The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR, Mol. Cell. Biol., 20, 2951–2958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Maglich, J. M., Parks, D. J., Moore, L. B., Collins, J. L., Goodwin, B., Billin, A. N., Stoltz, C. A., Kliewer, S. A., Lambert, M. H., Willson, T. M., and Moore, J. T. (2003) Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes, J. Biol. Chem., 278, 17277–17283.

    Article  CAS  PubMed  Google Scholar 

  18. Pustylnyak, V. O., Gulyaeva, L. F., and Lyakhovich, V. V. (2005) CAR expression and inducibility of CYP2B genes in liver of rats treated with PB-like inducers, Toxicology, 216, 147–153.

    Article  CAS  PubMed  Google Scholar 

  19. Forman, B. M., Tzameli, I., Choi, H. S., Chen, J., Simha, D., Seol, W., Evans, R. M., and Moore, D. D. (1998) Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta, Nature, 395, 612–615.

    Article  CAS  PubMed  Google Scholar 

  20. Swales, K., and Negishi, M. (2004) CAR, driving into the future, Mol. Endocrinol., 18, 1589–1598.

    Article  CAS  PubMed  Google Scholar 

  21. Sueyoshi, T., Moore, R., Pascussi, J. M., and Negishi, M. (2002) Direct expression of fluorescent protein-tagged nuclear receptor CAR in mouse liver, Methods Enzymol., 357, 205–213.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang, J., Huang, W., Chua, S. S., Wei, P., and Moore, D. D. (2002) Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR, Science, 298, 422–424.

    Article  CAS  PubMed  Google Scholar 

  23. Osabe, M., and Negishi, M. (2011) Active ERK1/2 protein interacts with the phosphorylated nuclear constitutive active/androstane receptor (CAR; NR1I3), repressing dephosphorylation and sequestering CAR in the cytoplasm, J. Biol. Chem., 286, 35763–35769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mutoh, S., Osabe, M., Inoue, K., Moore, R., Pedersen, L., Perera, L., Rebolloso, Y., Sueyoshi, T., and Negishi, M. (2009) Dephosphorylation of threonine 38 is required for nuclear translocation and activation of human xenobiotic receptor CAR (NR1I3), J. Biol. Chem., 284, 34785–34792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mutoh, S., Sobhany, M., Moore, R., Perera, L., Pedersen, L., Sueyoshi, T., and Negishi, M. (2013) Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling, Sci. Signal., 6, doi: 10.1126/scisignal.2003705.

  26. Sidhu, J. S., and Omiecinski, C. J. (1997) An okadaic acidsensitive pathway involved in the phenobarbital-mediated induction of CYP2B gene expression in primary rat hepatocyte cultures, J. Pharmacol. Exp. Ther., 282, 1122–1129.

    CAS  PubMed  Google Scholar 

  27. Hosseinpour, F., Moore, R., Negishi, M., and Sueyoshi, T. (2006) Serine 202 regulates the nuclear translocation of constitutive active/androstane receptor, Mol. Pharmacol., 69, 1095–1102.

    Article  CAS  PubMed  Google Scholar 

  28. Marc, N., Galisteo, M., Lagadic-Gossmann, D., Fautrel, A., Joannard, F., Guillouzo, A., and Corcos, L. (2000) Regulation of phenobarbital induction of the cytochrome P450 2b9/10 genes in primary mouse hepatocyte culture. Involvement of calciumand cAMP-dependent pathways, Eur. J. Biochem., 267, 963–970.

    Article  CAS  PubMed  Google Scholar 

  29. Sueyoshi, T., Kawamoto, T., Zelko, I., Honkakoski, P., and Negishi, M. (1999) The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene, J. Biol. Chem., 274, 6043–6046.

    Article  CAS  PubMed  Google Scholar 

  30. Honkakoski, P., and Negishi, M. (1997) Characterization of a phenobarbital-responsive enhancer module in mouse P450 Cyp2b10 gene, J. Biol. Chem., 272, 14943–14949.

    Article  CAS  PubMed  Google Scholar 

  31. Honkakoski, P., Zelko, I., Sueyoshi, T., and Negishi, M. (1998) The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene, Mol. Cell. Biol., 18, 5652–5658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Muangmoonchai, R., Smirlis, D., Wong, S. C., Edwards, M., Phillips, I. R., and Shephard, E. A. (2001) Xenobiotic induction of cytochrome P450 2B1 (CYP2B1) is mediated by the orphan nuclear receptor constitutive androstane receptor (CAR) and requires steroid coactivator 1 (SRC-1) and the transcription factor Sp1, Biochem. J., 355, 71–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Min, G., Kim, H., Bae, Y., Petz, L., and Kemper, J. K. (2002) Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR). CAR inhibits ER-mediated signaling pathway by squelching p160 coactivators, J. Biol. Chem., 277, 34626–34633.

    Article  CAS  PubMed  Google Scholar 

  34. Jyrkkarinne, J., Windshugel, B., Makinen, J., Ylisirnio, M., Perakyla, M., Poso, A., Sippl, W., and Honkakoski, P. (2005) Amino acids important for ligand specificity of the human constitutive androstane receptor, J. Biol. Chem., 280, 5960–5971.

    Article  PubMed  Google Scholar 

  35. Jyrkkarinne, J., Makinen, J., Gynther, J., Savolainen, H., Poso, A., and Honkakoski, P. (2003) Molecular determinants of steroid inhibition for the mouse constitutive androstane receptor, J. Med. Chem., 46, 4687–4695.

    Article  PubMed  Google Scholar 

  36. Laurenzana, E. M., Chen, T., Kannuswamy, M., Sell, B. E., Strom, S. C., Li, Y., and Omiecinski, C. J. (2012) The orphan nuclear receptor DAX-1 functions as a potent corepressor of the constitutive androstane receptor (NR1I3), Mol. Pharmacol., 82, 918–928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pascussi, J. M., Gerbal-Chaloin, S., Fabre, J. M., Maurel, P., and Vilarem, M. J. (2000) Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation, Mol. Pharmacol., 58, 1441–1450.

    CAS  PubMed  Google Scholar 

  38. Ooe, H., Kon, J., Oshima, H., and Mitaka, T. (2009) Thyroid hormone is necessary for expression of constitutive androstane receptor in rat hepatocytes, Drug Metab. Dispos., 37, 1963–1969.

    Article  CAS  PubMed  Google Scholar 

  39. Saito, K., Kobayashi, K., Mizuno, Y., Furihata, T., and Chiba, K. (2010) Constitutive androstane/active receptor is a target of retinoic acid receptor in humans, Biochem. Pharmacol., 80, 129–135.

    Article  CAS  PubMed  Google Scholar 

  40. Ding, X., Lichti, K., Kim, I., Gonzalez, F. J., and Staudinger, J. L. (2006) Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha, J. Biol. Chem., 281, 26540–26551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Takwi, A. A., Wang, Y. M., Wu, J., Michaelis, M., Cinatl, J., and Chen, T. (2014) miR-137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin-resistant neuroblastoma cells, Oncogene, 33, 3717–3729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tian, J., Huang, H., Hoffman, B., Liebermann, D. A., Ledda-Columbano, G. M., Columbano, A., and Locker, J. (2011) Gadd45ß is an inducible coactivator of transcription that facilitates rapid liver growth in mice, J. Clin. Invest., 121, 4491–4502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dong, J., Feldmann, G., Huang, J., Wu, S., Zhang, N., Comerford, S. A., Gayyed, M. F., Anders, R. A., Maitra, A., and Pan, D. (2007) Elucidation of a universal size-control mechanism in drosophila and mammals, Cell, 130, 1120–1133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kowalik, M. A., Saliba, C., Pibiri, M., Perra, A., Ledda Columbano, G. M., Sarotto, I., Ghiso, E., Giordano, S., and Columbano, A. (2011) Yes-associated protein regulation of adaptive liver enlargement and hepatocellular carcinoma development in mice, Hepatology, 53, 2086–2096.

    Article  CAS  PubMed  Google Scholar 

  45. He, T. C., Sparks, A. B., Rago, C., Hermeking, H., Zawel, L., da Costa, L. T., Morin, P. J., Vogelstein, B., and Kinzler, K. W. (1998) Identification of c-MYC as a target of the APC pathway, Science, 281, 1509–1512.

    Article  CAS  PubMed  Google Scholar 

  46. Tetsu, O., and McCormick, F. (1999) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells, Nature, 398, 422–426.

    Article  CAS  PubMed  Google Scholar 

  47. Devereux, T. R., Anna, C. H., Foley, J. F., White, C. M., Sills, R. C., and Barrett, J. C. (1999) Mutation of betacatenin is an early event in chemically induced mouse hepatocellular carcinogenesis, Oncogene, 18, 4726–4733.

    Article  CAS  PubMed  Google Scholar 

  48. Damalas, A., Kahan, S., Shtutman, M., Ben-Ze’ev, A., and Oren, M. (2001) Deregulated beta-catenin induces a p53and ARF-dependent growth arrest and cooperates with Ras in transformation, EMBO J., 20, 4912–4922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dong, B., Lee, J. S., Park, Y. Y., Yang, F., Xu, G., Huang, W., Finegold, M. J., and Moore, D. D. (2015) Activating CAR and ß-catenin induces uncontrolled liver growth and tumorigenesis, Nat. Commun., 6, 5944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Giera, S., Braeuning, A., Kohle, C., Bursch, W., Metzger, U., Buchmann, A., and Schwarz, M. (2010) Wnt/betacatenin signaling activates and determines hepatic zonal expression of glutathione S-transferases in mouse liver, Toxicol. Sci., 115, 22–33.

    Article  CAS  PubMed  Google Scholar 

  51. Braeuning, A., and Schwarz, M. (2010) ß-Catenin as a multilayer modulator of zonal cytochrome P450 expression in mouse liver, Biol. Chem., 391, 139–148.

    CAS  PubMed  Google Scholar 

  52. Gougelet, A., Torre, C., Veber, P., Sartor, C., Bachelot, L., Denechaud, P. D., Godard, C., Moldes, M., Burnol, A. F., Dubuquoy, C., Terris, B., Guillonneau, F., Ye, T., Schwarz, M., Braeuning, A., Perret, C., and Colnot, S. (2014) T-cell factor 4 and ß-catenin chromatin occupancies pattern zonal liver metabolism in mice, Hepatology, 59, 2344–2357.

    Article  CAS  PubMed  Google Scholar 

  53. Haupt, Y., Maya, R., Kazaz, A., and Oren, M. (1997) Mdm2 promotes the rapid degradation of p53, Nature, 387, 296–299.

    Article  CAS  PubMed  Google Scholar 

  54. Huang, W., Zhang, J., Washington, M., Liu, J., Parant, J. M., Lozano, G., and Moore, D. D. (2005) Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor, Mol. Endocrinol., 19, 1646–1653.

    Article  CAS  PubMed  Google Scholar 

  55. Blanco-Bose, W. E., Murphy, M. J., Ehninger, A., Offner, S., Dubey, C., Huang, W., Moore, D. D., and Trumpp, A. (2008) c-Myc and its target FoxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia, Hepatology, 48, 1302–1311.

    Article  CAS  PubMed  Google Scholar 

  56. Wang, I. C., Chen, Y. J., Hughes, D., Petrovic, V., Major, M. L., Park, H. J., Tan, Y., Ackerson, T., and Costa, R. H. (2005) Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase, Mol. Cell. Biol., 25, 10875–10894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bornstein, G., Bloom, J., Sitry-Shevah, D., Nakayama, K., Pagano, M., and Hershko, A. (2003) Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in Sphase, J. Biol. Chem., 278, 25752–25757.

    Article  CAS  PubMed  Google Scholar 

  58. Nakamura, N., Ramaswamy, S., Vazquez, F., Signoretti, S., Loda, M., and Sellers, W. R. (2000) Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN, Mol. Cell. Biol., 20, 8969–8982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Seoane, J., Le, H. V., Shen, L., Anderson, S. A., and Massague, J. (2004) Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation, Cell, 117, 211–223.

    Article  CAS  PubMed  Google Scholar 

  60. Essers, M. A., De Vries-Smits, L. M., Barker, N., Polderman, P. E., Burgering, B. M., and Korswagen, H. C. (2005) Functional interaction between beta-catenin and FOXO in oxidative stress signaling, Science, 308, 1181–1184.

    Article  CAS  PubMed  Google Scholar 

  61. Kodama, S., Koike, C., Negishi, M., and Yamamoto, Y. (2004) Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes, Mol. Cell. Biol., 24, 7931–7940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kachaylo, E. M., Yarushkin, A. A., and Pustylnyak, V. O. (2012) Constitutive androstane receptor activation by 2,4,6-triphenyldioxane-1,3 suppresses the expression of the gluconeogenic genes, Eur. J. Pharmacol., 679, 139–143.

    Article  CAS  PubMed  Google Scholar 

  63. Yarushkin, A. A., Kachaylo, E. M., and Pustylnyak, V. O. (2013) The constitutive androstane receptor activator 4[(4R,6R)-4,6-diphenyl-1,3-dioxan-2-yl]-N,N-dimethylaniline inhibits the gluconeogenic genes PEPCK and G6Pase through the suppression of HNF4α and FOXO1 transcriptional activity, J. Pharmacol., 168, 1923–1932.

    CAS  Google Scholar 

  64. Kazantseva, Y. A., Yarushkin, A. A., and Pustylnyak, V. O. (2014) CAR-mediated repression of Foxo1 transcriptional activity regulates the cell cycle inhibitor p21 in mouse livers, Toxicology, 321, 73–79.

    Article  CAS  PubMed  Google Scholar 

  65. Kato, J. Y., Matsushime, H., Hiebert, S. W., Ewen, M. E., and Sherr, C. J. (1993) Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase cDk4, Genes Dev., 7, 331–342.

    Article  CAS  PubMed  Google Scholar 

  66. Mittnacht, S. (1998) Control of pRB phosphorylation, Curr. Opin. Genet. Dev., 8, 21–27.

    Article  CAS  PubMed  Google Scholar 

  67. Ledda-Columbano, G. M., Pibiri, M., Loi, R., Perra, A., Shinozuka, H., and Columbano, A. (2000) Early increase in cyclin-D1 expression and accelerated entry of mouse hepatocytes into S phase after administration of the mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, Am. J. Pathol., 156, 91–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ledda-Columbano, G. M., Pibiri, M., Concas, D., Cossu, C., Tripodi, M., and Columbano, A. (2002) Loss of cyclin D1 does not inhibit the proliferative response of mouse liver to mitogenic stimuli, Hepatology, 36, 1098–1105.

    Article  CAS  PubMed  Google Scholar 

  69. Leone, G., De Gregori, J., Sears, R., Jakoi, L., and Nevins, J. R. (1997) Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F, Nature, 387, 422–426.

    Article  CAS  PubMed  Google Scholar 

  70. O’Donnell, K. A., Wentzel, E. A., Zeller, K. I., Dang, C. V., and Mendell, J. T. (2005) c-Myc-regulated microRNAs modulate E2F1 expression, Nature, 435, 839–843.

    Article  PubMed  Google Scholar 

  71. Wang, B., Hsu, S. H., Wang, X., Kutay, H., Bid, H. K., Yu, J., Ganju, R. K., Jacob, S. T., Yuneva, M., and Ghoshal, K. (2014) Reciprocal regulation of microRNA-122 and c-Myc in hepatocellular cancer: role of E2F1 and transcription factor dimerization partner 2, Hepatology, 59, 555–566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lagos-Quintana, M., Rauhut, R., Yalcin, A., Meyer, J., Lendeckel, W., and Tuschl, T. (2002) Identification of tissue-specific microRNAs from mouse, Curr. Biol., 12, 735–739.

    Article  CAS  PubMed  Google Scholar 

  73. Tsai, W. C., Hsu, S. D., Hsu, C. S., Lai, T. C., Chen, S. J., Shen, R., Huang, Y., Chen, H. C., Lee, C. H., Tsai, T. F., Hsu, M. T., Wu, J. C., Huang, H. D., Shiao, M. S., Hsiao, M., and Tsou, A. P. (2012) MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis, J. Clin. Invest., 122, 2884–2897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hsu, S. H., Wang, B., Kota, J., Yu, J., Costinean, S., Kutay, H., Yu, L., Bai, S., La Perle, K., Chivukula, R. R., Mao, H., Wei, M., Clark, K. R., Mendell, J. R., Caligiuri, M. A., Jacob, S. T., Mendell, J. T., and Ghoshal, K. (2012) Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver, J. Clin. Invest., 122, 2871–2883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kutay, H., Bai, S., Datta, J., Motiwala, T., Pogribny, I., Frankel, W., Jacob, S. T., and Ghoshal, K. (2006) Downregulation of miR-122 in the rodent and human hepatocellular carcinomas, J. Cell. Biochem., 99, 671–678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Coulouarn, C., Factor, V. M., Andersen, J. B., Durkin, M. E., and Thorgeirsson, S. S. (2009) Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties, Oncogene, 28, 3526–3536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kazantseva, Y. A., Yarushkin, A. A., Mostovich, L. A., Pustylnyak, Y. A., and Pustylnyak, V. O. (2015) Xenosensor CAR mediates down-regulation of miR-122 and up-regulation of miR-122 targets in the liver, Toxicol. Appl. Pharmacol., 288, 26–32.

    Article  CAS  PubMed  Google Scholar 

  78. Xu, H., He, J. H., Xiao, Z. D., Zhang, Q. Q., Chen, Y. Q., Zhou, H., and Qu, L. H. (2010) Liver-enriched transcription factors regulate microRNA-122 that targets CUTL1 during liver development, Hepatology, 52, 1431–1442.

    Article  CAS  PubMed  Google Scholar 

  79. Laudadio, I., Manfroid, I., Achouri, Y., Schmidt, D., Wilson, M. D., Cordi, S., Thorrez, L., Knoops, L., Jacquemin, P., Schuit, F., Pierreux, C. E., Odom, D. T., Peers, B., and Lemaigre, F. P. (2012) A feedback loop between the liver-enriched transcription factor network and miR-122 controls hepatocyte differentiation, Gastroenterology, 142, 119–129.

    Article  CAS  PubMed  Google Scholar 

  80. Li, Z. Y., Xi, Y., Zhu, W. N., Zeng, C., Zhang, Z. Q., Guo, Z. C., Hao, D. L., Liu, G., Feng, L., Chen, H. Z., Chen, F., Lv, X., Liu, D. P., and Liang, C. C. (2011) Positive regulation of hepatic miR-122 expression by HNF4α, J. Hepatol., 55, 602–611.

    Article  CAS  PubMed  Google Scholar 

  81. Hiebert, S. W., Lipp, M., and Nevins, J. R. (1989) E1Adependent trans-activation of the human MYC promoter is mediated by the E2F factor, Proc. Natl. Acad. Sci. USA, 86, 3594–3598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. De Smaele, E., Zazzeroni, F., Papa, S., Nguyen, D. U., Jin, R., Jones, J., Cong, R., and Franzoso, G. (2001). Induction of gadd45b by NF-κB downregulates pro-apoptotic JNK signaling, Nature, 414, 308–313.

    Article  PubMed  Google Scholar 

  83. Jin, R., De Smaele, E., Zazzeroni, F., Nguyen, D. U., Papa, S., Jones, J., Cox, C., Gelinas, C., and Franzoso, G. (2002) Regulation of the gadd45beta promoter by NFkappaB, DNA Cell Biol., 21, 491–503.

    Article  CAS  PubMed  Google Scholar 

  84. Yoo, J., Ghiassi, M., Jirmanova, L., Balliet, A. G., Hoffman, B., Fornace, A. J., Liebermann, D. A., Bottinger, E. P., and Roberts, A. B. (2003) Transforming growth factor-beta-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation, J. Biol. Chem., 278, 43001–43007.

    Article  CAS  PubMed  Google Scholar 

  85. Cretu, A., Sha, X., Tront, J., Hoffman, B., and Liebermann, D. A. (2009) Stress sensor Gadd45 genes as therapeutic targets in cancer, Cancer Ther., 7, 268–276.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Qiu, W., David, D., Zhou, B., Chu, P. G., Zhang, B., Wu, M., Xiao, J., Han, T., Zhu, Z., Wang, T., Liu, X., Lopez, R., Frankel, P., Jong, A., and Yen, Y. (2003) Down-regulation of growth arrest DNA damage-inducible gene 45beta expression is associated with human hepatocellular carcinoma, Am. J. Pathol., 162, 1961–1974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Qiu, W., Zhou, B., Zou, H., Liu, X., Chu, P. G., Lopez, R., Shih, J., Chung, C., and Yen, Y. (2004) Hypermethylation of growth arrest DNA damage-inducible gene 45 beta promoter in human hepatocellular carcinoma, Am. J. Pathol., 165, 1689–1699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Papa, S., Zazzeroni, F., Fu, Y. X., Bubici, C., Alvarez, K., Dean, K., Christiansen, P. A., Anders, R. A., and Franzoso, G. (2008) Gadd45beta promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling, J. Clin. Invest., 118, 1911–1923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Tian, J., Huang, H., Hoffman, B., Liebermann, D. A., Ledda-Columbano, G. M., Columbano, A., and Locker, J. (2011) Gadd45ß is an inducible coactivator of transcription that facilitates rapid liver growth in mice, J. Clin. Invest., 121, 4491–4502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Columbano, A., Ledda-Columbano, G. M., Pibiri, M., Cossu, C., Menegazzi, M., Moore, D. D., Huang, W., Tian, J., and Locker, J. (2005) Gadd45beta is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia, Hepatology, 42, 1118–1126.

    Article  CAS  PubMed  Google Scholar 

  91. Tian, J., Huang, H., Hoffman, B., Liebermann, D. A., Ledda-Columbano, G. M., Columbano, A., and Locker, J. (2011) Gadd45ß is an inducible coactivator of transcription that facilitates rapid liver growth in mice, J. Clin. Invest., 121, 4491–4502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Sabapathy, K., and Wagner, E. F. (2004) JNK2: a negative regulator of cellular proliferation, Cell Cycle, 3, 1520–1523.

    Article  CAS  PubMed  Google Scholar 

  93. Yi, Y. W., Kim, D., Jung, N., Hong, S. S., Lee, H. S., and Bae, I. (2000) Gadd45 family proteins are coactivators of nuclear hormone receptors, Biochem. Biophys. Res. Commun., 272, 193–198.

    Article  CAS  PubMed  Google Scholar 

  94. Yamamoto, Y., Moore, R., Flavell, R. A., Lu, B., and Negishi, M. (2010) Nuclear receptor CAR represses TNFalpha-induced cell death by interacting with the antiapoptotic GADD45B, PLoS One, 5, e10121.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to V. O. Pustylnyak.

Additional information

Original Russian Text © Y. A. Kazantseva, Y. A. Pustylnyak, V. O. Pustylnyak, 2016, published in Biokhimiya, 2016, Vol. 81, No. 4, pp. 476-486.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kazantseva, Y.A., Pustylnyak, Y.A. & Pustylnyak, V.O. Role of nuclear constitutive androstane receptor in regulation of hepatocyte proliferation and hepatocarcinogenesis. Biochemistry Moscow 81, 338–347 (2016). https://doi.org/10.1134/S0006297916040040

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297916040040

Keywords

Navigation