1887

Abstract

Hepatitis C virus (HCV) often causes persistent infection in humans. This could be due in part to the effect of viral proteins on cellular gene expression. Earlier observations suggest that the HCV core protein expressed from genotype 1a modulates important cellular genes at the transcriptional level, affects programmed cell death (apoptosis) and promotes cell growth. Recently, different groups of investigators have reported the translation of an ∼16 kDa protein (named F/ARFP/core+1 ORF) from an alternate open reading frame of the HCV core-encoding genomic region. The functional significance of this F protein is presently unknown. Thus, whether the F and core proteins have both shared and distinct functions was investigated here. The experimental observations suggested that the F protein does not significantly modulate c-, hTERT and p53 promoter activities, unlike the HCV core protein. Interestingly, the F protein repressed p21 expression. Further studies indicated that the F protein does not inhibit tumour necrosis factor alpha-mediated apoptosis of HepG2 cells or promote rat embryo fibroblast growth. Taken together, these results suggest that the F protein does not share major properties identified previously for the HCV core protein, other than regulating p21 expression.

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2004-08-01
2024-12-06
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References

  1. Alter M. J. 1995; Epidemiology of hepatitis C in the west. Semin Liver Dis 15:5–14 [CrossRef]
    [Google Scholar]
  2. Basu A., Meyer K., Ray R. B., Ray R. 2002; Hepatitis C virus core protein is necessary for the maintenance of immortalized human hepatocytes. Virology 298:53–62 [CrossRef]
    [Google Scholar]
  3. Bergqvist A., Rice C. M. 2001; Transcriptional activation of the interleukin-2 promoter by hepatitis C virus core protein. J Virol 75:772–781 [CrossRef]
    [Google Scholar]
  4. Boulant S., Becchi M., Penin F., Lavergne J. P. 2003; Unusual multiple recoding events leading to alternative forms of hepatitis C virus core protein from genotype 1b. J Biol Chem 278:45785–45792 [CrossRef]
    [Google Scholar]
  5. Chang J., Yang S. E., Cho Y.-G., Hwang S. B., Hahn Y. S., Sung Y. C. 1998; Hepatitis C virus from two different genotypes has an oncogenic potential but is not sufficient for transforming primary rat embryo fibroblasts in cooperation with the H-ras oncogene. J Virol 72:3060–3065
    [Google Scholar]
  6. Choi J., Xu Z., Ou J. H. 2003; Triple decoding of hepatitis C virus RNA by programmed translational frameshifting. Mol Cell Biol 23:1489–1497 [CrossRef]
    [Google Scholar]
  7. Choo Q. L., Kuo G., Weiner A. J., Overby L. R., Bradley D. W., Houghton M. 1989; Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362 [CrossRef]
    [Google Scholar]
  8. Clarke B. 1997; Molecular virology of hepatitis C virus. J Gen Virol 78:2397–2410
    [Google Scholar]
  9. Ghosh A. K., Majumder M., Steele R., Meyer K., Ray R., Ray R. B. 2000; Hepatitis C virus NS5A protein protects against TNF- α mediated apoptotic cell death. Virus Res 67:173–178 [CrossRef]
    [Google Scholar]
  10. Ghosh A. K., Steele R., Ray R. B. 2003; Modulation of human luteinizing hormone β gene transcription by MIP-2A. J Biol Chem 278:24033–24038 [CrossRef]
    [Google Scholar]
  11. Gosert R., Moradpour D. 2002; Reading between the lines: evidence for a new hepatitis C virus protein. Hepatology 36:757–760
    [Google Scholar]
  12. Grakoui A., Wychowski C., Lin C., Feinstone S. M., Rice C. M. 1993; Expression and identification of hepatitis C virus polyprotein cleavage products. J Virol 67:1385–1395
    [Google Scholar]
  13. Hijikata M., Kato N., Ootsuyama Y., Nakagawa M., Shimotohno K. 1991; Gene mapping of the putative structural region of the hepatitis C virus genome by in vitro processing analysis. Proc Natl Acad Sci U S A 88:5547–5551 [CrossRef]
    [Google Scholar]
  14. Jung E. Y., Lee M. N., Yang H. Y., Yu D., Jang K. L. 2001; The repressive activity of hepatitis C virus core protein on the transcription of p21waf1 is regulated by protein kinase A-mediated phosphorylation. Virus Res 79:109–115 [CrossRef]
    [Google Scholar]
  15. Kiyosawa K., Tanaka E. 2002; Hepatitis C virus in the etiology of hepatocellular carcinoma. In Viruses and Liver Cancer , 1st edn. pp  31–42 Edited by Tabor E. Amsterdam: Elsevier Science;
    [Google Scholar]
  16. Koike Y., Shiratori Y., Sato S. 8 other authors 2000; Risk factors for recurring hepatocellular carcinoma differ according to infected hepatitis virus – an analysis of 236 consecutive patients with a single lesion. Hepatology 32:1216–1223 [CrossRef]
    [Google Scholar]
  17. Lai M. M. C., Ware C. F. 2000; Hepatitis C virus core protein: possible roles in viral pathogenesis. Curr Top Microbiol Immunol 242:117–134
    [Google Scholar]
  18. Lee M. N., Jung E. Y., Kwun H. J., Jun H. K., Yu D. Y., Choi Y. H., Jang K. L. 2002; Hepatitis C virus core protein represses the p21 promoter through inhibition of a TGF- β pathway. J Gen Virol 83:2145–2151
    [Google Scholar]
  19. Logan J., Nicolas J. C., Topp W. C., Girard M., Shenk T., Levine A. J. 1981; Transformation by adenovirus early region 2A temperature-sensitive mutants and their revertants. Virology 115:419–422 [CrossRef]
    [Google Scholar]
  20. Marusawa H., Hijikata M., Chiba T., Shimotohno K. 1999; Hepatitis C virus core protein inhibits Fas- and tumor necrosis factor alpha-mediated apoptosis via NF- κ B activation. J Virol 73:4713–4720
    [Google Scholar]
  21. McLauchlan J. 2000; Properties of the hepatitis C virus core protein: a structural protein that modulates cellular processes. J Viral Hepat 7:2–14 [CrossRef]
    [Google Scholar]
  22. Moriya K., Fujie H., Shintani Y. 7 other authors 1998; The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 4:1065–1067 [CrossRef]
    [Google Scholar]
  23. Nguyen H., Mudryj M., Guadalupe M., Dandekar S. 2003; Hepatitis C virus core protein expression leads to biphasic regulation of the p21 cdk inhibitor and modulation of hepatocyte cell cycle. Virology 312:245–253 [CrossRef]
    [Google Scholar]
  24. Ray R. B., Ray R. 2001; Hepatitis C virus core protein: intriguing properties and functional relevance. FEMS Microbiol Lett 202:149–156 [CrossRef]
    [Google Scholar]
  25. Ray R. B., Lagging L. M., Meyer K., Steele R., Ray R. 1995a; Transcriptional regulation of cellular and viral promoters by the hepatitis C virus core protein. Virus Res 37:209–220 [CrossRef]
    [Google Scholar]
  26. Ray R. B., Steele R., Seftor E., Hendrix M. 1995b; Human breast carcinoma cells transfected with the gene encoding a c-myc promoter-binding protein (MBP-1) inhibits tumors in nude mice. Cancer Res 55:3747–3751
    [Google Scholar]
  27. Ray R. B., Lagging L. M., Meyer K., Ray R. 1996; Hepatitis C virus core protein cooperates with rats and transforms primary rat embryo fibroblasts to tumorigenic phenotype. J Virol 70:4438–4443
    [Google Scholar]
  28. Ray R. B., Steele R., Meyer K., Ray R. 1997; Transcriptional repression of p53 promoter by hepatitis C virus core protein. J Biol Chem 272:10983–10986 [CrossRef]
    [Google Scholar]
  29. Ray R. B., Meyer K., Steele R., Shrivastava A., Aggarwal B. B., Ray R. 1998a; Inhibition of tumor necrosis factor (TNF- α )-mediated apoptosis by hepatitis C virus core protein. J Biol Chem 273:2256–2259 [CrossRef]
    [Google Scholar]
  30. Ray R. B., Steele R., Meyer K., Ray R. 1998b; Hepatitis C virus core protein represses p21/WAF1/Cip1/Sid1 promoter activity. Gene 208:331–336 [CrossRef]
    [Google Scholar]
  31. Ray R. B., Steele R., Basu A., Meyer K., Majumder M., Ghosh A. K., Ray R. 2002; Distinct functional role of hepatitis C virus core protein on NF- κ B regulation is linked to genomic variation. Virus Res 87:21–29 [CrossRef]
    [Google Scholar]
  32. Roussel J., Pillez A., Montpellier C., Duverlie G., Cahour A., Dubuisson J., Wychowski C. 2003; Characterization of the expression of the hepatitis C virus F protein. J Gen Virol 84:1751–1759 [CrossRef]
    [Google Scholar]
  33. Saito I., Miyarnura T., Ohbayashi A. 8 other authors 1990; Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl Acad Sci U S A 87:6547–6549 [CrossRef]
    [Google Scholar]
  34. Shrivastava A., Manna S. K., Ray R., Aggarwal B. B. 1998; Ectopic expression of hepatitis C virus core protein differentially regulates nuclear transcription factors. J Virol 72:9722–9728
    [Google Scholar]
  35. Spanjaard R. A., Ikeda M., Lee P. J., Charpentier B., Chin W. W., Eberlein T. J. 1997; Specific activation of retinoic acid receptors (RARs) and retinoid X receptors reveals a unique role for RAR γ in induction of differentiation and apoptosis of S91 melanoma cells. J Biol Chem 272:18990–18999 [CrossRef]
    [Google Scholar]
  36. Srinivas R. V., Ray R. B., Meyer K., Ray R. 1996; Hepatitis C virus core protein inhibits human immunodeficiency virus type 1 replication. Virus Res 45:87–92 [CrossRef]
    [Google Scholar]
  37. Tsuchihara K., Hijikata M., Fukuda K., Kuriki T., Yamamoto N., Shimotohno K. 1999; Hepatitis C virus core protein regulates cell growth and signal transduction pathway transmitting growth stimuli. Virology 258:100–107 [CrossRef]
    [Google Scholar]
  38. Varaklioti A., Vassilaki N., Georgopoulou U., Mavromara P. 2002; Alternate translation occurs within the core coding region of the hepatitis C viral genome. J Biol Chem 277:17713–17721 [CrossRef]
    [Google Scholar]
  39. Vassilaki N., Mavromara P. 2003; Two alternative translation mechanisms are responsible for the expression of the HCV ARFP/F/core+1 coding open reading frame. J Biol Chem 278:40503–40513 [CrossRef]
    [Google Scholar]
  40. Walewski J. L., Keller T. R., Stump D. D., Branch A. D. 2001; Evidence for a new hepatitis C virus antigen encoded in an overlapping reading frame. RNA 7:710–721 [CrossRef]
    [Google Scholar]
  41. Xu Z., Choi T. S., Yen B., Lu W., Strohecker A., Govindarajan S., Chien D., Selby M., Ou J. H. 2001; Synthesis of a novel hepatitis C virus protein by ribosomal frame shift. EMBO J 20:3840–3848 [CrossRef]
    [Google Scholar]
  42. Xu Z., Choi J., Lu W., Ou J. 2003; Hepatitis C virus F protein is a short-lived protein associated with the endoplasmic reticulum. J Virol 77:1578–1583 [CrossRef]
    [Google Scholar]
  43. Yamanaka T., Kodama T., Doi T. 2002; Subcellular localization of HCV core protein regulates its ability for p53 activation and p21 suppression. Biochem Biophys Res Commun 294:528–534 [CrossRef]
    [Google Scholar]
  44. Yoshida T., Hanada T., Tokuhisa T., Kosai K. I., Sata M., Kohara M., Yoshimura A. 2002; Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation. J Exp Med 196:641–653 [CrossRef]
    [Google Scholar]
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