[Frontiers in Bioscience 3, d1241-1252, December 1, 1998]

	[Frontiers in Bioscience 3, d1241-1252, December 1, 1998] Reprints PubMed CAVEAT LECTOR
	INHIBITION OF INTERNAL ENTRY SITE (IRES)-MEDIATED TRANSLATION BY A SMALL YEAST RNA: A NOVEL STRATEGY TO BLOCK HEPATITIS C VIRUS PROTEIN SYNTHESIS Saumitra Das¹, Michael Ott², Akemi Yamane¹, Arun Venkatesan¹, Sanjeev Gupta² and Asim Dasgupta¹ Department of Microbiology, Molecular Genetics and Immunolog, UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1747¹, ²Department of Medicine, Albert Einstein, College of Medicine of Yeshiva University, Bronx, New York 10461-1602 Received 9/18/98 Accepted 9/23/98 7. REFERENCES 1. Agol, V.I. The 5´untranslated region of picornaviral genomes. Adv. Virus. Res. 40, 103-180. (1991) 2. Ali, N. and A. Siddiqui: The La antigen binds 5’ noncoding region of the hepatitis C virus RNA in the context of the initiator AUG codon and stimulates internal ribosome entry site mediated translation. Proc. Natl. Acad. Sci. USA 94, 2249-2254. (1997). 3. Anthony, D.D. and W.C. Merrick: Eukaryotic initiation factor (eIF)4F. Implications for a role in internal initiation of translation. J. Biol. Chem. 266, 10218-10226. (1991). 4. Baglioni, C. Simili, M. and D.A. Shafritz: Initiation activity of EMC virus RNA, binding to initiation factor eIF-4B and shut-off of host cell protein synthesis. Nature (London) 275, 240-243. (1978). 5. Bandopadhyay, P.K. Wang, C. and H. Lipton: Cap-independent translation by the 5´-untranslated region of Theiler's Murine Encephalomyelitis virus. J. Virol. 66, 6249-6256. (1992). 6. Belsham, G. J. and J.K. Brangwyn: A region of the 5´-noncoding region of foot-and-mouth disease virus RNA directs efficient internal initiation of protein synthesis within cells: involvement with the role of L protease in translational control. J. Virol. 64, 5389-5395. (1990). 7. Blyn, B.L. Chen, R. Semler, B.L. and E. Ehrenfeld: Host cell proteins binding to domain IV of the 5´-noncoding region of poliovirus RNA. J. Virol. 69, 4381-4389. (1995). 8. Blyn, B. L. Swiderek, K.M. Richards, O. Stahl, D.C. Semler, B.L. and E. Ehrenfeld: Poly(rC) binding protein 2 binds to stem-loop IV of the poliovirus RNA 5’ noncoding region: Identification by automated liquid chromatography - tandem mass spectrometry. Proc Natl Acad Sci. USA.93, 11115-11120. (1996). 9. Borman, A. Howell, M.T. Patton, J.G and R.J. Jackson: The involvement of a splicesome component in internal initiation of human rhinovirus RNA translation. J. Gen. Virol. 74, 1775-1788. (1993). 10. Bukh J. Purcell, R.H. and R.H. Miller: Sequence analysis of the 5’ non-coding region of hepatitis C virus. Proc Natl Acad Sci. USA 89, 4942 - 4946. (1992). 11. Chen, C. Y. and P. Sarnow: Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science 268, 415-417. (1995). 12. Coward, P. and A. Dasgupta: Yeast cells are incapable of translating RNAs containing the poliovirus 5´-untranslated region: evidence for a translational inhibitor. J. Virol. 66, 286-295. (1992). 13. Das, S. Kenan, D.J. Bocskai, D. Keene, J. D. and A. Dasgupta: Sequences within a small yeast RNA required for inhibition of internal initiation of translation: Interaction with La and other cellular proteins influences its inhibitory activity. J. Virol. 70, 1624-1632. (1996). 14. Das, S. Ott, M. Yamane, A. Tsai, W. Gromier, M. Lahser, F. Gupta, S. and A. Dasgupta: A small yeast RNA blocks hepatitis C virus (HCV) IRES-mediated translation and inhibits replication of a chimeric poliovirus under translational control of HCV IRES element. J. Virol. 72: (7); (1998). 15. Das, S. Coward, P. and A. Dasgupta: A small yeast RNA selectively blocks internal initiation of translation programmed by poliovirus RNA: specific interaction with cellular proteins that bind to viral 5´-untranslated region. J. Virol. 68, 7200-7211. (1994). 16. Ehrenfeld, E. Translational Control (Cold Spring Harbor Lab. Press, Plainview, NY),pp. 549-573. (1996). 17. Gamarnik, A.V. and R. Andino: Two functional complexes formed by KH domain containing proteins with the 5’noncoding region of poliovirus RNA. RNA 3, 882-892. (1997). 18. Gebhard, J. R. and E. Ehrenfeld: Specific interactions of HeLa cell proteins with proposed translation domains of the poliovirus 5´ noncoding region. J. Virol. 66, 3101-3109. (1992). 19. Glass, M. J. Jia, X. and D. Summers: Identification of the hepatitis A virus internal ribosome entry site: in vivo and in vitro analysis of bicistronic RNAs containing HAV 5´-noncoding region. Virology 193, 842-852. (1993). 20. Glass, M. J., Jia, X. and Summers, D. Identification of the hepatitis A virus internal ribosome entry site: in vivo and in vitro analysis of bicistronic RNAs containing HAV 5´-noncoding region. Virology 193, 842-852. (1993). 21. Grant CM, Hinnebusch, A.G. Effect of sequence context at stop codons on efficiency of reinitiation in GCN4 translational control. Mol Cell Biol. 14, 606-618. (1994). 22. Haller, A.A., andSemle, B.L. Stem-loop structure synergy in binding cellular proteins to the 5´-noncoding region of poliovirus RNA. Virology 206, 923-934. (1995). 23. Haller, A.A., Nguyen, J.H.C. and Semler, B.L. Minimum internal ribosome entry site required for poliovirus infectivity. J. Virol. 67, 7461-7471. (1993). 24. He, W.W., Lindzey, J. K. Prescott, J. L. Kumar, M.V. Tindall. D.J. The androgen receptor in the testicular feminized (Tfm) mouse may be a product of internal translation initiation. Receptor: 4(2), 121-134. (1994). 25. Hellen, C.U.T., Witherell, G.W. Schmid, M. Shin, S.H. Pestova, T.V. Gil, A. and Wimmer. E. A cytoplasmic 57 kd protein (p57) that is required for translation of picornavirus RNA by internal ribosome entry is identical to the nuclear polypyrimidine tract binding protein. Proc. Natl. Acad. Sci. USA. 90, 7642-7646. (1993). 26. Hinnebusch A. G. Translational control of GCN4: An in vivo barometer of initiation-factor activity. Trends Biochem Sci . 19, 409-414. (1994). 27. Izuka, N.L., and Sarnow, P. Cap-independent translation and internal initiation of translation in eukaryotic cellular mRNA molecules. Curr. Top. Microbiol. Immunol. 203, 155-177. (1994). 28. Izuka, N, L., Franzusoff, A. and Sarnow. P. Cap- dependent and cap independent translation by internal initiaion of mRNAs in cell free extracts prepared from Saccharomyces cerevisiae. Mol. Cell. Biol. 14, 7322-7330. (1994). 29. Jackson R.J., Hunt, S.L. Gibbs, C.L. Kamiski. A. Internal initiation of translation of picornavirus RNAs. Mol Biol Reports 19, 147-159. (1994). 30. Jackson R.J., Kaminski, A. Internal initiation of translation in eukaryotes: The picornavirus paradigm and beyond. RNA 1; 985-1000. (1995). 31. Jackson R.J., Hunt, S.L. Reynlds, J.E. Kaminski. A. Cap-dependent and cap-independent translation: Operational distinctions and mechanistic interpretations. Curr Topics Microbiol Immunol 203, 1-29. (1995). 32. Jang, S.K., Krausslich, H.G. Nicklin, M.J.H. Duke, G.M. Palmenberg, A.C. and Wimmer. E. A segment of the 5´ nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J. Virol. 62:, 2636-2643. (1988). 33. Kaminski A, Hunt, S.L. Gibbs, C.L. Jackson. R.J. Internal initiation of mRNA translation in eukaryotes. In: Setlow J, ed. Genetic engineering: Principles and Methods, Vol 16 New York: Plenum Press. pp 115-155. (1994). 34. Kozak M. An analysis of vertebrate mRNA sequences: Intimations of translational control. J Cell Biol 115, 887-903. (1991). 35. Lu, H. H, and Wimmer. E. Poliovirus chimeras replicating under the translational control of genetic elements of hepatitis C virus reveal unusual properties of internal ribosomal entry site of hepatitis C virus. Proc Natl Acad Sci. USA 93, 1412-1417. (1996). 36. Luz, N., and Beck. E. J. Interaction of a cellular 57 kilodalton protein with the internal translation initiation site of foot-and-mouth disease virus. Virology 65, 6486-6494. (1991). 37. Luz, N., and Beck. E.J. A cellular 57 kDa protein binds to two regions of the internal initiation site of foot and-mouth disease virus. Virology. 65, 6486-6494. (1990). 38. Macejak, D.G., and Sarnow. P. Internal initiation of translation mediated by the 5´-leader of a cellular mRNA. Nature (London). 353, 90-94. (1991). 39. Mathews, M.B., Interactions between viruses and the cellular machinery for protein synthesis. Traslational Control, Cold Spring Harbor Laboratory Press. Plainview, New York: 505-549. (1996). 40. McBartney, S., and Sarnow. P. Evidence for involvement of trans-acting factors in selection of the AUG start codon during eukaryotic translational initiation. Mol. Cell Biol. 16, 3523-3534. (1996). 41. Meerovitch, K., Svitkin, Y.V. Lee, H.S. Lejbkowicz, F. Kenan, D. J. Chan, E.K.L. Agol, V.I. Keene, J. D. and Sonenberg. N. La autoantigen enhances and corrects aberrant translation of poliovirus RNA in reticulocyte lysate. J. Virol. 67, 3798-3807. (1993). 42. Mizutani, T., Kato, N. Saito, S. Ikeda, M. Sugiyama, K. and Shimotohno. K. Characterization of hepatitis C virus replication in cloned cells obtained from human T-cell leukemia virus type 1- infected cell line MT-2. J.Virol. 70, 7219-223. (1996). 43. Myer, K., Petersen, A. Niepmann, M. and Beck, E. Interaction of eukaryotic initiation factor eIF-4B with a picornavirus internal translation initiation site. J. Viro l. 69, 2819-2824. (1995). 44. Najita, L., and Sarnow. P. Oxidation-reduction sensitive interaction of a cellular 50-kD protein with an RNA hairpin in the 5´-noncoding region of the poliovirus genome. Proc. Natl. Acad. Sci. USA 87, 5846-5850. (1990). 45. Oh, S.K., Scott, M.P. and Sarnow, P. Homeotic gene Antennapedia mRNA contains 5´-noncoding sequences that confer translational initiation by internal ribosome binding. Genes Dev. 6, 1643-1653. (1992). 46. Parsley, T.B., Towner, J.S. Blyn, L.B. Ehrenfled, E. and Semler, B.L. Poly (rc) binding protein 2 forms a ternary complex wiwth the 5´-terminal sequence of poliovirus RNA and the viral 3CD proteinase. RNA 3; 1124-1134. (1997). 47.Pause, A., Methot, N. Svitkin, Y. Merrick, W.C. and Sonenberg, N. Dominant negative mutants of mammalian translation initiation factor eIF-4A define critical role for eIF-4F in cap-dependent and cap-independent initiation of translation. EMBO J. 13, 1205-1215. (1994). 48. Pelletier, J., and Sonenberg, N. Internal initiation of translation of euakryotic mRNA directed by a sequence derived from poliovirus RNA. Nature (London) 334, 320-325. (1988). 49..Pelletier, J., Flynn, M.E. Kaplan, G. Racaniello, V.R. and Sonenberg, N. Mutational analysis of upstram AUG codons of poliovirus RNA. J. Virol. 62, 4486-4492. (1988). 50. Percy, N., Belsham, G.J. Brangwyn, J. K. Sullivan, M., Stone, D.M. and Almond, J.W. Intracellular modifications induced by poliovirus reduce the requirement for structural motifs in the 5´-noncoding region of the genome involved in internal initiation of protein synthesis. J. Virol. 66, 1695-1701. (1992). 51. Pestova, T.V., Hellen, C.U.T. and Shatsky, I.N. Canonical eukaryotic initiation factors determine initiation of translation by internal ribosomal entry. Mol. Cell. Biol. 16, 6859-6869 (1996). 52. Reynolds, J. E., Kaminski, A. Kttinen, H.J. Grace K. Clarke, B.E. Rowlands, D.J. and Jackson, R.J. Unique features of internal initiation of translation of hepatitis C virus translation. EMBO. J. 14, 6010-6020. (1995). 53. Rueckert, R.R. Picornavriuses and their replication, p. 705-738. In B.N. Fields (ed.), Virology. Raven Press, New York. (1985) 54. Schultz, D.B., Hardin, C. C. and Lemon, S. M. Specific interaction of glyceraldehyde 3-phosphate dehydrogenase with the 5’-nontranslated RNA of hepatitis A virus. J. Biol.Chem. 271, 14134-14142. (1996). 55. Sonenberg, N., and Meerorich, K. Translation of poliovirus mRNA. Enzyme 44, 278-291.(1990). 56. Svitkin, Y.V., Merovitch, K. Lee, H.S. Dholakia, J. N. Kenan, D.J. Agol, V.I. and Sonenberg, N. Internal translation initiation on poliovirus RNA: further characterization of La function in poliovirus translation in vitro. J. Virol. 68, 1544-1550. (1994). 57. Tsukiyama-Kohara, K.I. Zuka, N. Kohara, M. and Nomoto. A. Internal ribosome entry site within hepatitis C virus RNA. J. Virol. 66, 1476-1483. (1992). 58. Vagner S., Gensac, M. C. Maret, A. Baynard, F. Amalric, F. Prats, H. Prats, A.C. Alternative translation of human fibroblast growth factor 2 mRNA occurs by internal entry of ribosomes. Mol Cell Biol 15, 35-44. (1995). 59. Wang, C., Sarnow, P. and Siddiqui. A. Translation of human hepatitis C virus RNA in cultured cells is mediated by an internal ribosome-binding mechanism. J. Virol. 67, 3338-3344. (1993). 60. Wang, C., Sarnow, P. and Siddiqui. A. A conserved helical element is essential for internal initiation of translation of hepatitis C virus RNA. J. Virol. 68, 7301-7307. (1994). 61. Yen, J.H, Chang, S.C. Hu, C.R. Chu, S.C. Lin, S.S., Hsieh, Y.S. and Chang, M.F. Cellular proteins specifically bind to the 5’-noncoding region of hepatitis C virus RNA. Virology 208, 723-732. (1995).

[Frontiers in Bioscience 3, d1241-1252, December 1, 1998]
Reprints
PubMed
CAVEAT LECTOR

INHIBITION OF INTERNAL ENTRY SITE (IRES)-MEDIATED TRANSLATION BY A SMALL YEAST RNA: A NOVEL STRATEGY TO BLOCK HEPATITIS C VIRUS PROTEIN SYNTHESIS

Saumitra Das¹, Michael Ott², Akemi Yamane¹, Arun Venkatesan¹, Sanjeev Gupta² and Asim Dasgupta¹

Department of Microbiology, Molecular Genetics and Immunolog, UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1747¹, ²Department of Medicine, Albert Einstein, College of Medicine of Yeshiva University, Bronx, New York 10461-1602

Received 9/18/98 Accepted 9/23/98

7. REFERENCES

1. Agol, V.I. The 5´untranslated region of picornaviral genomes. Adv. Virus. Res. 40, 103-180. (1991)

2. Ali, N. and A. Siddiqui: The La antigen binds 5’ noncoding region of the hepatitis C virus RNA in the context of the initiator AUG codon and stimulates internal ribosome entry site mediated translation. Proc. Natl. Acad. Sci. USA 94, 2249-2254. (1997).

3. Anthony, D.D. and W.C. Merrick: Eukaryotic initiation factor (eIF)4F. Implications for a role in internal initiation of translation. J. Biol. Chem. 266, 10218-10226. (1991).

4. Baglioni, C. Simili, M. and D.A. Shafritz: Initiation activity of EMC virus RNA, binding to initiation factor eIF-4B and shut-off of host cell protein synthesis. Nature (London) 275, 240-243. (1978).

5. Bandopadhyay, P.K. Wang, C. and H. Lipton: Cap-independent translation by the 5´-untranslated region of Theiler's Murine Encephalomyelitis virus. J. Virol. 66, 6249-6256. (1992).

6. Belsham, G. J. and J.K. Brangwyn: A region of the 5´-noncoding region of foot-and-mouth disease virus RNA directs efficient internal initiation of protein synthesis within cells: involvement with the role of L protease in translational control. J. Virol. 64, 5389-5395. (1990).

7. Blyn, B.L. Chen, R. Semler, B.L. and E. Ehrenfeld: Host cell proteins binding to domain IV of the 5´-noncoding region of poliovirus RNA. J. Virol. 69, 4381-4389. (1995).

8. Blyn, B. L. Swiderek, K.M. Richards, O. Stahl, D.C. Semler, B.L. and E. Ehrenfeld: Poly(rC) binding protein 2 binds to stem-loop IV of the poliovirus RNA 5’ noncoding region: Identification by automated liquid chromatography - tandem mass spectrometry. Proc Natl Acad Sci. USA.93, 11115-11120. (1996).

9. Borman, A. Howell, M.T. Patton, J.G and R.J. Jackson: The involvement of a splicesome component in internal initiation of human rhinovirus RNA translation. J. Gen. Virol. 74, 1775-1788. (1993).

10. Bukh J. Purcell, R.H. and R.H. Miller: Sequence analysis of the 5’ non-coding region of hepatitis C virus. Proc Natl Acad Sci. USA 89, 4942 - 4946. (1992).

11. Chen, C. Y. and P. Sarnow: Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science 268, 415-417. (1995).

12. Coward, P. and A. Dasgupta: Yeast cells are incapable of translating RNAs containing the poliovirus 5´-untranslated region: evidence for a translational inhibitor. J. Virol. 66, 286-295. (1992).

13. Das, S. Kenan, D.J. Bocskai, D. Keene, J. D. and A. Dasgupta: Sequences within a small yeast RNA required for inhibition of internal initiation of translation: Interaction with La and other cellular proteins influences its inhibitory activity. J. Virol. 70, 1624-1632. (1996).

14. Das, S. Ott, M. Yamane, A. Tsai, W. Gromier, M. Lahser, F. Gupta, S. and A. Dasgupta: A small yeast RNA blocks hepatitis C virus (HCV) IRES-mediated translation and inhibits replication of a chimeric poliovirus under translational control of HCV IRES element. J. Virol. 72: (7); (1998).

15. Das, S. Coward, P. and A. Dasgupta: A small yeast RNA selectively blocks internal initiation of translation programmed by poliovirus RNA: specific interaction with cellular proteins that bind to viral 5´-untranslated region. J. Virol. 68, 7200-7211. (1994).

16. Ehrenfeld, E. Translational Control (Cold Spring Harbor Lab. Press, Plainview, NY),pp. 549-573. (1996).

17. Gamarnik, A.V. and R. Andino: Two functional complexes formed by KH domain containing proteins with the 5’noncoding region of poliovirus RNA. RNA 3, 882-892. (1997).

18. Gebhard, J. R. and E. Ehrenfeld: Specific interactions of HeLa cell proteins with proposed translation domains of the poliovirus 5´ noncoding region. J. Virol. 66, 3101-3109. (1992).

19. Glass, M. J. Jia, X. and D. Summers: Identification of the hepatitis A virus internal ribosome entry site: in vivo and in vitro analysis of bicistronic RNAs containing HAV 5´-noncoding region. Virology 193, 842-852. (1993).

20. Glass, M. J., Jia, X. and Summers, D. Identification of the hepatitis A virus internal ribosome entry site: in vivo and in vitro analysis of bicistronic RNAs containing HAV 5´-noncoding region. Virology 193, 842-852. (1993).

21. Grant CM, Hinnebusch, A.G. Effect of sequence context at stop codons on efficiency of reinitiation in GCN4 translational control. Mol Cell Biol. 14, 606-618. (1994).

22. Haller, A.A., andSemle, B.L. Stem-loop structure synergy in binding cellular proteins to the 5´-noncoding region of poliovirus RNA. Virology 206, 923-934. (1995).

23. Haller, A.A., Nguyen, J.H.C. and Semler, B.L. Minimum internal ribosome entry site required for poliovirus infectivity. J. Virol. 67, 7461-7471. (1993).

24. He, W.W., Lindzey, J. K. Prescott, J. L. Kumar, M.V. Tindall. D.J. The androgen receptor in the testicular feminized (Tfm) mouse may be a product of internal translation initiation. Receptor: 4(2), 121-134. (1994).

25. Hellen, C.U.T., Witherell, G.W. Schmid, M. Shin, S.H. Pestova, T.V. Gil, A. and Wimmer. E. A cytoplasmic 57 kd protein (p57) that is required for translation of picornavirus RNA by internal ribosome entry is identical to the nuclear polypyrimidine tract binding protein. Proc. Natl. Acad. Sci. USA. 90, 7642-7646. (1993).

26. Hinnebusch A. G. Translational control of GCN4: An in vivo barometer of initiation-factor activity. Trends Biochem Sci . 19, 409-414. (1994).

27. Izuka, N.L., and Sarnow, P. Cap-independent translation and internal initiation of translation in eukaryotic cellular mRNA molecules. Curr. Top. Microbiol. Immunol. 203, 155-177. (1994).

28. Izuka, N, L., Franzusoff, A. and Sarnow. P. Cap- dependent and cap independent translation by internal initiaion of mRNAs in cell free extracts prepared from Saccharomyces cerevisiae. Mol. Cell. Biol. 14, 7322-7330. (1994).

29. Jackson R.J., Hunt, S.L. Gibbs, C.L. Kamiski. A. Internal initiation of translation of picornavirus RNAs. Mol Biol Reports 19, 147-159. (1994).

30. Jackson R.J., Kaminski, A. Internal initiation of translation in eukaryotes: The picornavirus paradigm and beyond. RNA 1; 985-1000. (1995).

31. Jackson R.J., Hunt, S.L. Reynlds, J.E. Kaminski. A. Cap-dependent and cap-independent translation: Operational distinctions and mechanistic interpretations. Curr Topics Microbiol Immunol 203, 1-29. (1995).

32. Jang, S.K., Krausslich, H.G. Nicklin, M.J.H. Duke, G.M. Palmenberg, A.C. and Wimmer. E. A segment of the 5´ nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J. Virol. 62:, 2636-2643. (1988).

33. Kaminski A, Hunt, S.L. Gibbs, C.L. Jackson. R.J. Internal initiation of mRNA translation in eukaryotes. In: Setlow J, ed. Genetic engineering: Principles and Methods, Vol 16 New York: Plenum Press. pp 115-155. (1994).

34. Kozak M. An analysis of vertebrate mRNA sequences: Intimations of translational control. J Cell Biol 115, 887-903. (1991).

35. Lu, H. H, and Wimmer. E. Poliovirus chimeras replicating under the translational control of genetic elements of hepatitis C virus reveal unusual properties of internal ribosomal entry site of hepatitis C virus. Proc Natl Acad Sci. USA 93, 1412-1417. (1996).

36. Luz, N., and Beck. E. J. Interaction of a cellular 57 kilodalton protein with the internal translation initiation site of foot-and-mouth disease virus. Virology 65, 6486-6494. (1991).

37. Luz, N., and Beck. E.J. A cellular 57 kDa protein binds to two regions of the internal initiation site of foot and-mouth disease virus. Virology. 65, 6486-6494. (1990).

38. Macejak, D.G., and Sarnow. P. Internal initiation of translation mediated by the 5´-leader of a cellular mRNA. Nature (London). 353, 90-94. (1991).

39. Mathews, M.B., Interactions between viruses and the cellular machinery for protein synthesis. Traslational Control, Cold Spring Harbor Laboratory Press. Plainview, New York: 505-549. (1996).

40. McBartney, S., and Sarnow. P. Evidence for involvement of trans-acting factors in selection of the AUG start codon during eukaryotic translational initiation. Mol. Cell Biol. 16, 3523-3534. (1996).

41. Meerovitch, K., Svitkin, Y.V. Lee, H.S. Lejbkowicz, F. Kenan, D. J. Chan, E.K.L. Agol, V.I. Keene, J. D. and Sonenberg. N. La autoantigen enhances and corrects aberrant translation of poliovirus RNA in reticulocyte lysate. J. Virol. 67, 3798-3807. (1993).

42. Mizutani, T., Kato, N. Saito, S. Ikeda, M. Sugiyama, K. and Shimotohno. K. Characterization of hepatitis C virus replication in cloned cells obtained from human T-cell leukemia virus type 1- infected cell line MT-2. J.Virol. 70, 7219-223. (1996).

43. Myer, K., Petersen, A. Niepmann, M. and Beck, E. Interaction of eukaryotic initiation factor eIF-4B with a picornavirus internal translation initiation site. J. Viro l. 69, 2819-2824. (1995).

44. Najita, L., and Sarnow. P. Oxidation-reduction sensitive interaction of a cellular 50-kD protein with an RNA hairpin in the 5´-noncoding region of the poliovirus genome. Proc. Natl. Acad. Sci. USA 87, 5846-5850. (1990).

45. Oh, S.K., Scott, M.P. and Sarnow, P. Homeotic gene Antennapedia mRNA contains 5´-noncoding sequences that confer translational initiation by internal ribosome binding. Genes Dev. 6, 1643-1653. (1992).

46. Parsley, T.B., Towner, J.S. Blyn, L.B. Ehrenfled, E. and Semler, B.L. Poly (rc) binding protein 2 forms a ternary complex wiwth the 5´-terminal sequence of poliovirus RNA and the viral 3CD proteinase. RNA 3; 1124-1134. (1997).

47.Pause, A., Methot, N. Svitkin, Y. Merrick, W.C. and Sonenberg, N. Dominant negative mutants of mammalian translation initiation factor eIF-4A define critical role for eIF-4F in cap-dependent and cap-independent initiation of translation. EMBO J. 13, 1205-1215. (1994).

48. Pelletier, J., and Sonenberg, N. Internal initiation of translation of euakryotic mRNA directed by a sequence derived from poliovirus RNA. Nature (London) 334, 320-325. (1988).

49..Pelletier, J., Flynn, M.E. Kaplan, G. Racaniello, V.R. and Sonenberg, N. Mutational analysis of upstram AUG codons of poliovirus RNA. J. Virol. 62, 4486-4492. (1988).

50. Percy, N., Belsham, G.J. Brangwyn, J. K. Sullivan, M., Stone, D.M. and Almond, J.W. Intracellular modifications induced by poliovirus reduce the requirement for structural motifs in the 5´-noncoding region of the genome involved in internal initiation of protein synthesis. J. Virol. 66, 1695-1701. (1992).

51. Pestova, T.V., Hellen, C.U.T. and Shatsky, I.N. Canonical eukaryotic initiation factors determine initiation of translation by internal ribosomal entry. Mol. Cell. Biol. 16, 6859-6869 (1996).

52. Reynolds, J. E., Kaminski, A. Kttinen, H.J. Grace K. Clarke, B.E. Rowlands, D.J. and Jackson, R.J. Unique features of internal initiation of translation of hepatitis C virus translation. EMBO. J. 14, 6010-6020. (1995).

53. Rueckert, R.R. Picornavriuses and their replication, p. 705-738. In B.N. Fields (ed.), Virology. Raven Press, New York. (1985)

54. Schultz, D.B., Hardin, C. C. and Lemon, S. M. Specific interaction of glyceraldehyde 3-phosphate dehydrogenase with the 5’-nontranslated RNA of hepatitis A virus. J. Biol.Chem. 271, 14134-14142. (1996).

55. Sonenberg, N., and Meerorich, K. Translation of poliovirus mRNA. Enzyme 44, 278-291.(1990).

56. Svitkin, Y.V., Merovitch, K. Lee, H.S. Dholakia, J. N. Kenan, D.J. Agol, V.I. and Sonenberg, N. Internal translation initiation on poliovirus RNA: further characterization of La function in poliovirus translation in vitro. J. Virol. 68, 1544-1550. (1994).

57. Tsukiyama-Kohara, K.I. Zuka, N. Kohara, M. and Nomoto. A. Internal ribosome entry site within hepatitis C virus RNA. J. Virol. 66, 1476-1483. (1992).

58. Vagner S., Gensac, M. C. Maret, A. Baynard, F. Amalric, F. Prats, H. Prats, A.C. Alternative translation of human fibroblast growth factor 2 mRNA occurs by internal entry of ribosomes. Mol Cell Biol 15, 35-44. (1995).

59. Wang, C., Sarnow, P. and Siddiqui. A. Translation of human hepatitis C virus RNA in cultured cells is mediated by an internal ribosome-binding mechanism. J. Virol. 67, 3338-3344. (1993).

60. Wang, C., Sarnow, P. and Siddiqui. A. A conserved helical element is essential for internal initiation of translation of hepatitis C virus RNA. J. Virol. 68, 7301-7307. (1994).

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