1887

Abstract

Abnormal accumulation of -catenin is considered to be a strong driving force in hepatocellular carcinogenesis; however, the mechanism of -catenin accumulation in tumours is unclear. Here, it was demonstrated that hepatitis B virus X protein (HBx) differentially regulates the level of -catenin through two ubiquitin-dependent proteasome pathways depending on p53 status. In the presence of p53, HBx downregulated -catenin through the activation of a p53–Siah-1 proteasome pathway. For this purpose, HBx upregulated Siah-1 expression at the transcriptional level via activation of p53. In the absence of p53, however, HBx stabilized -catenin through the inhibition of a glycogen synthase kinase-3-dependent pathway. Interestingly, HBx variants with a Pro-101 to Ser substitution were unable to activate p53 and thus could stabilize -catenin irrespective of p53 status. Based on these findings, a model of -catenin regulation by HBx is proposed whereby the balance between the two opposite activities of HBx determines the overall expression level of -catenin. Differential regulation of -catenin by HBx depending on host (p53 status) and viral factors (HBx sequence variation) helps not only to explain the observation that cancers accumulating -catenin also exhibit a high frequency of p53 mutations but also to understand the contradictory reports on the roles of HBx during hepatocellular carcinogenesis.

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2007-08-01
2020-10-28
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References

  1. Aberle H., Bauer A., Stappert J., Kispert A., Kemler R. 1997; β -Catenin is a target for the ubiquitin–proteasome pathway. EMBO J 16:3797–3804 [CrossRef]
    [Google Scholar]
  2. Ahn J. Y., Chung E. Y., Kwun H. J., Lee C. W., Sung Y. C., Jang K. L. 2002; Dual effects of hepatitis B virus X protein on the regulation of cell-cycle control depending on the status of cellular p53. J Gen Virol 83:2765–2772
    [Google Scholar]
  3. Albrechtsen N., Dornreiter I., Grosse F., Kim E., Wiesmuller L., Deppert W. 1999; Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53. Oncogene 18:7706–7717 [CrossRef]
    [Google Scholar]
  4. Benn J., Su F., Doria M., Schneider R. J. 1996; 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. J Virol 70:4978–4985
    [Google Scholar]
  5. Block T. M., Mehta A. S., Fimmel C. J., Jordan R. 2003; Molecular viral oncology of hepatocellular carcinoma. Oncogene 22:5093–5107 [CrossRef]
    [Google Scholar]
  6. Cagatay T., Ozturk M. 2002; p53 mutation as a source of aberrant β -catenin accumulation in cancer cells. Oncogene 21:7971–7980 [CrossRef]
    [Google Scholar]
  7. Calender A., Billaud M., Aubry J. P., Banchereau J., Vuillaume M., Lenoir G. M. 1987; Epstein–Barr virus (EBV) induces expression of B-cell activation markers on in vitro infection of EBV-negative B-lymphoma cells. Proc Natl Acad Sci U S A 84:8060–8064 [CrossRef]
    [Google Scholar]
  8. Cha M. Y., Kim C. M., Park Y. M., Ryu W. S. 2004; Hepatitis B virus X protein is essential for the activation of Wnt/ β -catenin signaling in hepatoma cells. Hepatology 39:1683–1693 [CrossRef]
    [Google Scholar]
  9. Ciechanover A., Ben-Saadon R. 2004; N-terminal ubiquitination: more protein substrates join in. Trends Cell Biol 14:103–106 [CrossRef]
    [Google Scholar]
  10. Colnot S., Decaens T., Niwa-Kawakita M., Godard C., Hamard G., Kahn A., Giovannini M., Perret C. 2004; Liver-targeted disruption of Apc in mice activates β -catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci U S A 101:17216–17221 [CrossRef]
    [Google Scholar]
  11. Cui J., Zhou X., Liu Y., Tang Z., Romeih M. 2003; Wnt signaling in hepatocellular carcinoma: analysis of mutation and expression of β -catenin, T-cell factor-4 and glycogen synthase kinase 3- β genes. J Gastroenterol Hepatol 18:280–287 [CrossRef]
    [Google Scholar]
  12. de La Coste A., Romagnolo B., Billuart P., Renard C. A., Buendia M. A., Soubrane O., Fabre M., Chelly J., Beldjord C. other authors 1998; Somatic mutations of the β -catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A 95:8847–8851 [CrossRef]
    [Google Scholar]
  13. Desbois-Mouthon C., Cadoret A., Blivet-Van Eggelpoel M. J., Bertrand F., Cherqui G., Perret C., Capeau J. 2001; Insulin and IGF-1 stimulate the β -catenin pathway through two signalling cascades involving GSK-3 β inhibition and Ras activation. Oncogene 20:252–259 [CrossRef]
    [Google Scholar]
  14. Devereux T. R., Stern M. C., Flake G. P., Yu M. C., Zhang Z. Q., London S. J., Taylor J. A. 2001; CTNNB1 mutations and β -catenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1. Mol Carcinog 31:68–73 [CrossRef]
    [Google Scholar]
  15. Ding Q., Xia W., Liu J. C., Yang J. Y., Lee D. F., Xia J., Bartholomeusz G., Li Y., Pan Y. other authors 2005; Erk associates with and primes GSK-3 β for its inactivation resulting in upregulation of β -catenin. Mol Cell 19:159–170 [CrossRef]
    [Google Scholar]
  16. Elmore L. W., Hancock A. R., Chang S. F., Wang X. W., Chang S., Callahan C. P., Geller D. A., Will H., Harris C. C. 1997; Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proc Natl Acad Sci U S A 94:14707–14712 [CrossRef]
    [Google Scholar]
  17. Endo K., Ueda T., Ueyama J., Ohta T., Terada T. 2000; Immunoreactive E-cadherin, α -catenin, β -catenin, and γ -catenin proteins in hepatocellular carcinoma: relationships with tumor grade, clinicopathologic parameters, and patients' survival. Hum Pathol 31:558–565 [CrossRef]
    [Google Scholar]
  18. Everly D. N., Kusano S., Raab-Traub N. 2004; Accumulation of cytoplasmic β -catenin and nuclear glycogen synthase kinase 3 β in Epstein–Barr virus-infected cells. J Virol 78:11648–11655 [CrossRef]
    [Google Scholar]
  19. Fiucci G., Beaucourt S., Duflaut D., Lespagnol A., Stumptner-Cuvelette P., Geant A., Buchwalter G., Tuynder M., Susini L. other authors 2004; Siah-1b is a direct transcriptional target of p53: identification of the functional p53 responsive element in the siah-1b promoter. Proc Natl Acad Sci U S A 101:3510–3515 [CrossRef]
    [Google Scholar]
  20. Gottardi C. J., Gumbiner B. M. 2001; Adhesion signaling: how β -catenin interacts with its partners. Curr Biol 11:R792–R794 [CrossRef]
    [Google Scholar]
  21. He T. C., Sparks A. B., Rago C., Hermeking H., Zawel L., da Costa L. T., Morin P. J., Vogelstein B., Kinzler K. W. 1998; Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512 [CrossRef]
    [Google Scholar]
  22. Holnthoner W., Pillinger M., Groger M., Wolff K., Ashton A. W., Albanese C., Neumeister P., Pestell R. G., Petzelbauer P. 2002; Fibroblast growth factor-2 induces Lef/Tcf-dependent transcription in human endothelial cells. J Biol Chem 277:45847–45853 [CrossRef]
    [Google Scholar]
  23. Hu G., Fearon E. R. 1999; Siah-1 N-terminal RING domain is required for proteolysis function, and C-terminal sequences regulate oligomerization and binding to target proteins. Mol Cell Biol 19:724–732
    [Google Scholar]
  24. Iwai A., Marusawa H., Matsuzawa S., Fukushima T., Hijikata M., Reed J. C., Shimotohno K., Chiba T. 2004; Siah-1L, a novel transcript variant belonging to the human Siah family of proteins, regulates β -catenin activity in a p53-dependent manner. Oncogene 23:7593–7600 [CrossRef]
    [Google Scholar]
  25. Jang K. L., Shackelford J., Seo S. Y., Pagano J. S. 2005; Up-regulation of β -catenin by a viral oncogene correlates with inhibition of the seven in absentia homolog 1 in B lymphoma cells. Proc Natl Acad Sci U S A 102:18431–18436 [CrossRef]
    [Google Scholar]
  26. Janus F., Albrechtsen N., Knippschild U., Wiesmuller L., Grosse F., Deppert W. 1999; Different regulation of the p53 core domain activities 3′-to-5′ exonuclease and sequence-specific DNA binding. Mol Cell Biol 19:2155–2168
    [Google Scholar]
  27. Jia L., Wang X. W., Harris C. C. 1999; Hepatitis B virus X protein inhibits nucleotide excision repair. Int J Cancer 80:875–879 [CrossRef]
    [Google Scholar]
  28. Katoh H., Shibata T., Kokubu A., Ojima H., Kosuge T., Kanai Y., Hirohashi S. 2006; Genetic inactivation of the APC gene contributes to the malignant progression of sporadic hepatocellular carcinoma: a case report. Genes Chromosomes Cancer 45:1050–1057 [CrossRef]
    [Google Scholar]
  29. Kim C. M., Koike K., Saito I., Miyamura T., Jay G. 1991; HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351:317–320 [CrossRef]
    [Google Scholar]
  30. Kwun H. J., Jang K. L. 2004; Natural variants of hepatitis B virus X protein have differential effects on the expression of cyclin-dependent kinase inhibitor p21 gene. Nucleic Acids Res 32:2202–2213 [CrossRef]
    [Google Scholar]
  31. Laurent-Puig P., Legoix P., Bluteau O., Belghiti J., Franco D., Binot F., Monges G., Thomas G., Bioulac-Sage P., Zucman-Rossi J. 2001; Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology 120:1763–1773 [CrossRef]
    [Google Scholar]
  32. Lee Y. H., Yun Y. 1998; HBx protein of hepatitis B virus activates Jak1-STAT signaling. J Biol Chem 273:25510–25515 [CrossRef]
    [Google Scholar]
  33. Lee C. W., Sorensen T. S., Shikama N., La Thangue N. B. 1998; Functional interplay between p53 and E2F through co-activator p300. Oncogene 16:2695–2710 [CrossRef]
    [Google Scholar]
  34. Levine A. J. 1997; p53, the cellular gatekeeper for growth and division. Cell 88:323–331 [CrossRef]
    [Google Scholar]
  35. Liu J., Stevens J., Rote C. A., Yost H. J., Hu Y., Neufeld K. L., White R. L., Matsunami N. 2001; Siah-1 mediates a novel β -catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Mol Cell 7:927–936 [CrossRef]
    [Google Scholar]
  36. Maguire H. F., Hoeffler J. P., Siddiqui A. 1991; HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein–protein interactions. Science 252:842–844 [CrossRef]
    [Google Scholar]
  37. Matsuo K., Satoh S., Okabe H., Nomura A., Maeda T., Yamaoka Y., Ikai I. 2003; SIAH1 inactivation correlates with tumor progression in hepatocellular carcinomas. Genes Chromosomes Cancer 36:283–291 [CrossRef]
    [Google Scholar]
  38. Matsuzawa S. I., Reed J. C. 2001; Siah-1, SIP, and Ebi collaborate in a novel pathway for β -catenin degradation linked to p53 responses. Mol Cell 7:915–926 [CrossRef]
    [Google Scholar]
  39. Morgan S. E., Kim R., Wang P. C., Bhat U. G., Kusumoto H., Lu T., Beck W. T. 2000; Differences in mutant p53 protein stability and functional activity in teniposide-sensitive and -resistant human leukemic CEM cells. Oncogene 19:5010–5019 [CrossRef]
    [Google Scholar]
  40. Nelson W. J., Nusse R. 2004; Convergence of Wnt, β -catenin, and cadherin pathways. Science 303:1483–1487 [CrossRef]
    [Google Scholar]
  41. Park U. S., Park S. K., Lee Y. I., Park J. G., Lee Y. I. 2000; Hepatitis B virus-X protein upregulates the expression of p21waf1/cip1 and prolongs G1 to S transition via a p53-independent pathway in human hepatoma cells. Oncogene 19:3384–3394 [CrossRef]
    [Google Scholar]
  42. Paterlini P., Poussin K., Kew M., Franco D., Brechot C. 1995; Selective accumulation of the X transcript of hepatitis B virus in patients negative for hepatitis B surface antigen with hepatocellular carcinoma. Hepatology 21:313–321
    [Google Scholar]
  43. Peifer M., Polakis P. 2000; Wnt signaling in oncogenesis and embryogenesis – a look outside the nucleus. Science 287:1606–1609 [CrossRef]
    [Google Scholar]
  44. Polakis P. 2007; The many ways of Wnt in cancer. Curr Opin Genet Dev 17:45–51 [CrossRef]
    [Google Scholar]
  45. Prost S., Ford J. M., Taylor C., Doig J., Harrison D. J. 1998; Hepatitis B x protein inhibits p53-dependent DNA repair in primary mouse hepatocytes. J Biol Chem 273:33327–33332 [CrossRef]
    [Google Scholar]
  46. Qadri I., Maguire H. F., Siddiqui A. 1995; Hepatitis B virus transactivator protein X interacts with the TATA-binding protein. Proc Natl Acad Sci U S A 92:1003–1007 [CrossRef]
    [Google Scholar]
  47. Sadot E., Geiger B., Oren M., Ben-Ze'ev A. 2001; Down-regulation of β -catenin by activated p53. Mol Cell Biol 21:6768–6781 [CrossRef]
    [Google Scholar]
  48. Satoh S., Daigo Y., Furukawa Y., Kato T., Miwa N., Nishiwaki T., Kawasoe T., Ishiguro H., Fujita M. other authors 2000; AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 24:245–250 [CrossRef]
    [Google Scholar]
  49. Shih W. L., Kuo M. L., Chuang S. E., Cheng A. L., Doong S. L. 2000; Hepatitis B virus X protein inhibits transforming growth factor- β -induced apoptosis through the activation of phosphatidylinositol 3-kinase pathway. J Biol Chem 275:25858–25864 [CrossRef]
    [Google Scholar]
  50. Slagle B. L., Lee T. H., Medina D., Finegold M. J., Butel J. S. 1996; Increased sensitivity to the hepatocarcinogen diethylnitrosamine in transgenic mice carrying the hepatitis B virus X gene. Mol Carcinog 15:261–269 [CrossRef]
    [Google Scholar]
  51. Sohn S., Jaitovitch-Groisman I., Benlimame N., Galipeau J., Batist G., Alaoui-Jamali M. A. 2000; Retroviral expression of the hepatitis B virus x gene promotes liver cell susceptibility to carcinogen-induced site specific mutagenesis. Mutat Res 460:17–28 [CrossRef]
    [Google Scholar]
  52. Taniguchi K., Roberts L. R., Aderca I. N., Dong X., Qian C., Murphy L. M., Nagorney D. M., Burgart L. J., Roche P. C. other authors 2002; Mutational spectrum of β -catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 21:4863–4871 [CrossRef]
    [Google Scholar]
  53. Terradillos O., Billet O., Renard C. A., Levy R., Molina T., Briand P., Buendia M. A. 1997; The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice. Oncogene 14:395–404 [CrossRef]
    [Google Scholar]
  54. Tetsu O., McCormick F. 1999; β -Catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398:422–426 [CrossRef]
    [Google Scholar]
  55. van de Wetering M., Oosterwegel M., Dooijes D., Clevers H. 1991; Identification and cloning of TCF-1, a T lymphocyte-specific transcription factor containing a sequence-specific HMG box. EMBO J 10:123–132
    [Google Scholar]
  56. Wong C. M., Fan S. T., Ng I. O. 2001; β -Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer 92:136–145 [CrossRef]
    [Google Scholar]
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