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Functional inactivation but not structural mutation of p53 causes liver cancer

Nature Genetics volume 9, pages 41–47 (1995)Cite this article

Abstract

Structural mutations in the p53 gene are seen in virtually every form of human cancer. To determine whether such mutations are important for initiating tumorigenesis, we have been studying hepatocellular carcinoma, in which most cases are associated with chronic hepatitis B virus infections. Using a transgenic mouse model where expression of a single HBV gene product, the HBx protein, induces progressive changes in the liver, we show that tumour development correlates precisely with p53 binding to HBx in the cytoplasm and complete blockage of p53 entry into the nucleus. Analysis of tumour cell DMA shows no evidence for p53 mutation, except in advanced tumours where a small proportion of cells may have acquired specific base substitutions. Our results suggest that genetic changes in p53 are late events which may contribute to tumour progression.

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References

  1. Harris, C.C. & Hollstein, M. Clinical implications of the p53 tumor-suppressor gene. New Engl. J. Med. 329, 1318–1327 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Jay, G. et al. A common transformation-related protein in murine sarcomas and leukemias. Cold Spring Harbor Symp. Quant. Biol. 44, 659–664 (1979).

    Article  Google Scholar 

  3. DeLeo, A.B. et al. Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc. natn. Acad. Sci. U.S.A. 76, 2420–2424 (1979).

    Article  CAS  Google Scholar 

  4. Lane, D.P. & Crawford, L.V. T Antigen is bound to a host protein in SV40-transformed cells. Nature 278, 261–263 (1979).

    Article  CAS  PubMed  Google Scholar 

  5. Linzer, D.I. & Levine, A.J. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17, 43–52 (1979).

    Article  CAS  PubMed  Google Scholar 

  6. Dippold, W.G., Jay, G., DeLeo, A.B., Khoury, G. & Old, L.J. p53transformation-related protein: Detection by monoclonal antibody in mouse and human cells. Proc. natn. Acad. Sci. U.S.A. 78, 1695–1699 (1981).

    Article  CAS  Google Scholar 

  7. Crawford, L.V., Pim, D.C., Gurney, E.G., Goodfellow, P. & Taylor-Papadimitriou, J. Detection of a common feature in several human tumor cell lines — a 53,000-dalton protein. Proc. natn. Acad. Sci. U.S.A. 78, 41–45 (1981).

    Article  CAS  Google Scholar 

  8. Sarnow, P., Ho, Y.S., Williams, J. & Levine, A.J., Adenovirus E1b-58 kd tumor antigen and SV40 large tumor antigen are physically associated with the same 54 kd cellular protein in transformed cells. Cell 28, 387–394 (1982).

    Article  CAS  PubMed  Google Scholar 

  9. Szekely, L., Selivanova, G., Magnusson, K.P., Klein, G. & Wiman, K.G. EBNA-5, an Epstein-Barrvirus-encoded nuclear antigen, binds to the retinoblastoma and p53 proteins. Proc. natn. Acad. Sci. U.S.A. 90, 5455–5459 (1993).

    Article  CAS  Google Scholar 

  10. Werness, B.A., Levine, A.J. & Howley, P.M. Association of human papillomavlrus types 16 and 18 E6 proteins with p53. Science 248, 76–79 (1990).

    Article  CAS  PubMed  Google Scholar 

  11. Feitelson, M.A., Zhu, M., Duan, L.X. & London, W.T. Hepatitis Bx antigen and p53 are associated in vitro and in liver tissues from patients with primary hepatocellular carcinoma. Oncogene 8, 1109–1117 (1993).

    CAS  PubMed  Google Scholar 

  12. Levine, A.J., Momand, J. & Findlay, C.A. The p53 tumour suppressor gene. Nature 351, 453–456 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Momand, J., Zambetti, G.P., Olson, D., George, D.L. & Levine, A.J. The mdm-2 oncogene product forms a complex with the p53 protein and Inhibits p53-mediated transactivation. Cell 69, 1237–1245 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Barak, Y. & Oren, M. Enhanced binding of a 95 kDa protein to p53 in cells undergoing p53-mediated growth arrest. EMBO J. 11, 2115–2121 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pietenpol, J.A. & Vogelstein, B. Tumour suppressor genes: no room at the p53 inn. Nature 365, 17–18 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Beasley, R.P. & Hwang, L.Y. in Viral hepatitis and liver disease. (eds Vyas, G.N.,Dienstag. J.L. & Hoofnagle, J.H.) 209–224 (Grune & Stratton, NewYork, 1984).

    Google Scholar 

  17. Tiollais, P., Pourcel, C. & Dejean, A. The hepatitis B virus. Nature 317, 489–495 (1985).

    Article  CAS  PubMed  Google Scholar 

  18. Popper, H., Shafritz, D.A. & Hoofnagle, J.H. Relation of the hepatitis B virus carrier state to hepatocellular carcinoma. Hepatology 7, 764–772 (1987).

    Article  CAS  PubMed  Google Scholar 

  19. Hsu, I.C., Metcalf, R.A., Sun, T., Welsh, J.A., Wang, N.J. & Harris, C.C. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350, 427–428 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Bressac, B., Kew, M.C., Wand, J.R. & Ozturk, M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350, 429–431 (1991).

    Article  CAS  PubMed  Google Scholar 

  21. Hosono, S., Lee, C.-S., Chou, M.-J., Yang, C.-S. & Shin, C. Molecular analysis of the p53 alleles In primary hepatocellular carcinomas and cell lines. Oncogene 6, 237–243 (1991).

    CAS  PubMed  Google Scholar 

  22. Buetow, K.H., Sheffield, V.C., Zhu, M., Zhou, T., Shen, M.F. & Hino, O. Low frequency of p53 mutations observed in a diverse collection of primary hepatocellular carcinomas. Proc. natn. Acad. Sci. U.S.A. 89, 9622–9626 (1992).

    Article  CAS  Google Scholar 

  23. Sheu, J.C., Huang, G.T., Lee, P.H., Chung, J.C., Chou, H.C. & Lai, M.Y. Mutation of p53 gene in hepatocellular carcinoma in Taiwan. Cancer Res. 52, 6098–6100 (1992).

    CAS  PubMed  Google Scholar 

  24. Nishida, N., Fukuda, Y., Kokuryu, H., Toguchida, J., Yandell, D.W. & Ikenega, M. Role and mutational heterogeneity of the p53 gene in hepatocellular carcinoma. Cancer Res. 53, 368–372 (1993).

  25. Unsal, H., Yakicier, C., Marcais, C., Kew, M., Volkmann, M. & Zentgraf, H. Genetic heterogeneity of hepatocellular carcinoma. Proc. natn. Acad. Sci. U.S.A. 91, 822–826 (1994).

    Article  CAS  Google Scholar 

  26. Twu, J.S. & Schloemer, R.H. Transcriptional trans-activating function of hepatitis B virus. J. Virol. 61, 3448–3453 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Seto, E., Yen, T., Peterlin, B.M. & Ou, J. Trans-activation of the human immunodeficiency virus long terminal repeat by the hepatitis B virus X protein. Proc. natn. Acad. Sci. U.S.A. 85, 8286–8290 (1988).

    Article  CAS  Google Scholar 

  28. Spandau, D.F. & Lee, C.H. Trans-activation of viral enhancers by the hepatitis B virus X protein. J. Virol. 62, 427–434 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Colgrove, R., Simon, G. & Ganem, D. Transcriptional activation of homologous and heterologous genes by the hepatitis B virus X gene product in cells permissive for viral replication. J. Virol. 63, 4019–4026 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kim, C.-M., Koike, K., Saito, I., Miyamura, T. & Jay, G., The HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351, 317–320 (1991).

    Article  CAS  PubMed  Google Scholar 

  31. Lee, T.-H., Finegold, M.J., Shen, R.F., DeMayo, J.L., Woo, S.L.C. & Butel, J.S. Hepatitis B virus transact!vator X protein is not tumorigenic In transgenic mice. J. Virol. 64, 5939–5947 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Feitelson, M.A. & Clayton, M.M. X antigen polypeptides in the sera of hepatitis B virus-infected patients. Virology 177, 367–371 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Kekule, A.S., Lauer, U., Weiss, L., Luber, B. & Hofschneider, P.H. Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature 361, 742–745 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. Cross, J.C., Wen, P. & Rutter, W.J. Transactivation by hepatitis B virus X protein is promiscuous and dependent on mitogen-activated cellular serine/ threonine kinases. Proc. natn. Acad. Sci. U.S.A. 90, 8078–8082 (1993).

    Article  CAS  Google Scholar 

  35. Ullrich, S.J. et al. Phosphorylation at Ser-15 and Ser-392 In mutant p53 molecules from human tumors is altered compared to wild-type p53. Proc. natn. Acad. Sci. U.S.A. 90, 5954–5958 (1993).

    Article  CAS  Google Scholar 

  36. Harlow, E., Crawford, L.V., Pirn, D.C. & Williamson, N.A. Monoclonal antibodies specific for simian virus 40 tumor antigens. J. Virol. 39, 861–869 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hsu, H.-C., Tseng, H.-J., Lai, P.-L., Lee, P.-H. & Peng, S.-Y. Expression of p53 gene In 184 unlfocal hepatocellular carcinomas: association with tumor growth and invasiveness. Cancer Res. 53, 4691–4694 (1993).

    CAS  PubMed  Google Scholar 

  38. Schek, N., Bartenschlager, R., Kuhn, C. & Schaller, H. Phosphorylation and rapid turnover of hepatitis B virus X-protein expressed in HepG2 cells from a recombinant vaccinia virus. Oncogene 6, 1735–1744 (1991).

    CAS  PubMed  Google Scholar 

  39. Jay, G., Khoury, G., DeLeo, A.B., Dippold, W.G. & Old, L.J. p53transformation-related protein: Detection of an associated phosphotransferase activity. Proc. natn. Acad. Sci. U.S.A. 78, 2931–2936 (1981).

    Google Scholar 

  40. Ullrich, S.J., Anderson, C.W., Mercer, W.E. & Appella, E. The p53 tumor suppressor protein, a modulator of cell proliferation. J. biol. Chem. 267, 15259–15262 (1992).

    CAS  PubMed  Google Scholar 

  41. Wang, X.W., Forrester, K., Yeh, H., Feitelson, M.A., Gu, J.-R. & Harris, C.C. Hepatitis B virus X protein Inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc. natn. Acad. Sci. U.S.A 91, 2230–2234 (1994).

    Article  CAS  Google Scholar 

  42. Tur-Kaspa, R. et al. Alpha Interferon suppresses hepatitis B virus enhancer activity and reduces viral gene transcription. J. Virol. 64, 1821–1824 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Horisberger, M.A. & DeStaritzky, K. A recombinant human interferon-alpha B/D hybrid with a broad host-range. J. gen. Virol. 68, 945–948 (1987).

    Article  CAS  PubMed  Google Scholar 

  44. Gangemi, J.D., Lazdins, J., Dietrich, F.M., Matter, A., Poncioni, B. & Hochkeppel, H.-K. Antiviral activity of anovel recombinant human interferon-alpha B/D hybrid. J. Interferon Res. 9, 227–237 (1989).

    Article  CAS  PubMed  Google Scholar 

  45. Perrillo, R.P. Interferon in the management of chronic hepatitis B. Dig. Dis. Sci. 38, 577–593 (1993).

    Article  CAS  PubMed  Google Scholar 

  46. Orita, M., Suzuki, Y., Sekiya, T. & Hayashi, K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5, 874–879 (1989).

    Article  CAS  PubMed  Google Scholar 

  47. Tanaka, S., Toh, Y., Adachi, E., Matsumato, T., Mori, R. & Sujimachi, K. Tumor progression in hepatocellular carcinoma may be mediated by p53 mutation. Cancer Res. 53, 2884–2887 (1993).

    CAS  PubMed  Google Scholar 

  48. Oda, T., Tsuda, H., Scarpa, A., Sakamoto, M. & Hirohashi, S. p53 gene mutation spectrum in hepatocellular carcinoma. Cancer Res. 52, 6358–6364 (1992).

    CAS  PubMed  Google Scholar 

  49. Teramoto, T., Satonaka, K., Kitazawa, S., Fujimori, T., Kozaburo, H. & Maeda, S. . p53 gene abnormalities are closely related to hepatoviral infections and occur at a late stage of hepatocarcinogenesis. Cancer Res. 54, 231–235 (1994).

    CAS  PubMed  Google Scholar 

  50. Greenblatt, M.S., Bennett, W.P., Hollstein, M. & Harris, C.C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesls. Cancer Res. 54, 4855–4878 (1994).

    CAS  PubMed  Google Scholar 

  51. Halevy, O., Rodel, J., Peled, A. & Oren, M. Frequent p53 mutations in chemically induced murine fibrosarcoma. Oncogene 6, 1593–1600 (1991).

    CAS  PubMed  Google Scholar 

  52. Fujiyama, A., Miyanohara, A., Nozaki, C., Yoneyama, T., Ohtomo, N. & Matsubara, K. Cloning and structural analyses of hepatitis B virus DNAs, subtype adr. Nucl. Acids Res. 11, 4601–4610 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gutierrez, M.I. et al. Infrequent p53 mutation In mouse tumors with deregulated myc. Cancer Res. 52, 1032–1035 (1992).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Virology, Jerome H. Holland Laboratory, Rockville, Maryland, 20855, USA

    Hiroyuki Ueda, Stephen J. Ullrich, Catherine A. Kappel, Lien Ngo & Gilbert Jay

  2. Greenville Hospital System, Clemson University Clemson, South Carolina, 29634, USA

    J. David Gangemi

  3. Department of Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA

    Mark A. Feitelson

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Ueda, H., Ullrich, S., Gangemi, J. et al. Functional inactivation but not structural mutation of p53 causes liver cancer. Nat Genet 9, 41–47 (1995). https://doi.org/10.1038/ng0195-41

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