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. 1996 Nov;70(11):7984–7991. doi: 10.1128/jvi.70.11.7984-7991.1996

Linkage between reovirus-induced apoptosis and inhibition of cellular DNA synthesis: role of the S1 and M2 genes.

K L Tyler 1, M K Squier 1, A L Brown 1, B Pike 1, D Willis 1, S M Oberhaus 1, T S Dermody 1, J J Cohen 1
PMCID: PMC190871  PMID: 8892922

Abstract

The mammalian reoviruses are capable of inhibiting cellular DNA synthesis and inducing apoptosis. Reovirus strains type 3 Abney (T3A) and type 3 Dearing (T3D) inhibit cellular DNA synthesis and induce apoptosis to a substantially greater extent than strain type 1 Lang (T1L). We used T1L x T3A and T1L x T3D reassortant viruses to identify viral genes associated with differences in the capacities of reovirus strains to elicit these cellular responses to viral infection. We found that the S1 and M2 genome segments determine differences in the capacities of both T1L x T3A and T1L x T3D reassortant viruses to inhibit cellular DNA synthesis and to induce apoptosis. These genes encode viral outer-capsid proteins that play important roles in viral attachment and disassembly. To extend these findings, we used field isolate strains of reovirus to determine whether the strain-specific differences in inhibition of cellular DNA synthesis and induction of apoptosis are also associated with viral serotype, a property determined by the S1 gene. In these experiments, type 3 field isolate strains were found to inhibit cellular DNA synthesis and to induce apoptosis to a greater extent than type 1 field isolate strains. Statistical analysis of these data indicate a significant correlation between the capacity of T1L x T3A and T1L x T3D reassortant viruses and field isolate strains to inhibit cellular DNA synthesis and to induce apoptosis. These findings suggest that reovirus-induced inhibition of cellular DNA synthesis and induction of apoptosis are linked and that both phenomena are induced by early steps in the viral replication cycle.

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Selected References

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  1. Bangaru B., Morecki R., Glaser J. H., Gartner L. M., Horwitz M. S. Comparative studies of biliary atresia in the human newborn and reovirus-induced cholangitis in weanling mice. Lab Invest. 1980 Nov;43(5):456–462. [PubMed] [Google Scholar]
  2. Bodkin D. K., Fields B. N. Growth and survival of reovirus in intestinal tissue: role of the L2 and S1 genes. J Virol. 1989 Mar;63(3):1188–1193. doi: 10.1128/jvi.63.3.1188-1193.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chaly N., Johnstone M., Hand R. Alterations in nuclear structure and function in reovirus-infected cells. Clin Invest Med. 1979;2(4):141–152. [PubMed] [Google Scholar]
  4. Colombel M., Olsson C. A., Ng P. Y., Buttyan R. Hormone-regulated apoptosis results from reentry of differentiated prostate cells onto a defective cell cycle. Cancer Res. 1992 Aug 15;52(16):4313–4319. [PubMed] [Google Scholar]
  5. Coombs K. M., Fields B. N., Harrison S. C. Crystallization of the reovirus type 3 Dearing core. Crystal packing is determined by the lambda 2 protein. J Mol Biol. 1990 Sep 5;215(1):1–5. doi: 10.1016/s0022-2836(05)80089-0. [DOI] [PubMed] [Google Scholar]
  6. Cox D. C., Shaw J. E. Inhibition of the initiation of cellular DNA synthesis after reovirus infection. J Virol. 1974 Mar;13(3):760–761. doi: 10.1128/jvi.13.3.760-761.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Danis C., Mabrouk T., Garzon S., Lemay G. Establishment of persistent reovirus infection in SC1 cells: absence of protein synthesis inhibition and increased level of double-stranded RNA-activated protein kinase. Virus Res. 1993 Mar;27(3):253–265. doi: 10.1016/0168-1702(93)90037-n. [DOI] [PubMed] [Google Scholar]
  8. Dermody T. S., Nibert M. L., Bassel-Duby R., Fields B. N. Sequence diversity in S1 genes and S1 translation products of 11 serotype 3 reovirus strains. J Virol. 1990 Oct;64(10):4842–4850. doi: 10.1128/jvi.64.10.4842-4850.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Drayna D., Fields B. N. Biochemical studies on the mechanism of chemical and physical inactivation of reovirus. J Gen Virol. 1982 Nov;63(Pt 1):161–170. doi: 10.1099/0022-1317-63-1-161. [DOI] [PubMed] [Google Scholar]
  10. Drayna D., Fields B. N. Genetic studies on the mechanism of chemical and physical inactivation of reovirus. J Gen Virol. 1982 Nov;63(Pt 1):149–159. doi: 10.1099/0022-1317-63-1-149. [DOI] [PubMed] [Google Scholar]
  11. Ensminger W. D., Tamm I. Cellular DNA and protein synthesis in reovirus-infected L cells. Virology. 1969 Oct;39(2):357–360. doi: 10.1016/0042-6822(69)90062-2. [DOI] [PubMed] [Google Scholar]
  12. Ensminger W. D., Tamm I. The step in cellular DNA synthesis blocked by reovirus infection. Virology. 1969 Dec;39(4):935–938. doi: 10.1016/0042-6822(69)90032-4. [DOI] [PubMed] [Google Scholar]
  13. Fields B. N., Joklik W. K. Isolation and preliminary genetic and biochemical characterization of temperature-sensitive mutants of reovirus. Virology. 1969 Mar;37(3):335–342. doi: 10.1016/0042-6822(69)90217-7. [DOI] [PubMed] [Google Scholar]
  14. Freeman R. S., Estus S., Johnson E. M., Jr Analysis of cell cycle-related gene expression in postmitotic neurons: selective induction of Cyclin D1 during programmed cell death. Neuron. 1994 Feb;12(2):343–355. doi: 10.1016/0896-6273(94)90276-3. [DOI] [PubMed] [Google Scholar]
  15. Gaulton G. N., Greene M. I. Inhibition of cellular DNA synthesis by reovirus occurs through a receptor-linked signaling pathway that is mimicked by antiidiotypic, antireceptor antibody. J Exp Med. 1989 Jan 1;169(1):197–211. doi: 10.1084/jem.169.1.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Haller B. L., Barkon M. L., Vogler G. P., Virgin H. W., 4th Genetic mapping of reovirus virulence and organ tropism in severe combined immunodeficient mice: organ-specific virulence genes. J Virol. 1995 Jan;69(1):357–364. doi: 10.1128/jvi.69.1.357-364.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hand R., Kasupski G. DNA and histone synthesis in reovirus-infected cells. J Gen Virol. 1978 Jun;39(3):437–448. doi: 10.1099/0022-1317-39-3-437. [DOI] [PubMed] [Google Scholar]
  18. Hand R., Tamm I. Initiation of DNA replication in mammalian cells and its inhibition by reovirus infection. J Mol Biol. 1974 Jan 15;82(2):175–183. doi: 10.1016/0022-2836(74)90339-8. [DOI] [PubMed] [Google Scholar]
  19. Hooper J. W., Fields B. N. Monoclonal antibodies to reovirus sigma 1 and mu 1 proteins inhibit chromium release from mouse L cells. J Virol. 1996 Jan;70(1):672–677. doi: 10.1128/jvi.70.1.672-677.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hooper J. W., Fields B. N. Role of the mu 1 protein in reovirus stability and capacity to cause chromium release from host cells. J Virol. 1996 Jan;70(1):459–467. doi: 10.1128/jvi.70.1.459-467.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hrdy D. B., Rosen L., Fields B. N. Polymorphism of the migration of double-stranded RNA genome segments of reovirus isolates from humans, cattle, and mice. J Virol. 1979 Jul;31(1):104–111. doi: 10.1128/jvi.31.1.104-111.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hrdy D. B., Rubin D. H., Fields B. N. Molecular basis of reovirus neurovirulence: role of the M2 gene in avirulence. Proc Natl Acad Sci U S A. 1982 Feb;79(4):1298–1302. doi: 10.1073/pnas.79.4.1298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Johnson N. L., Gardner A. M., Diener K. M., Lange-Carter C. A., Gleavy J., Jarpe M. B., Minden A., Karin M., Zon L. I., Johnson G. L. Signal transduction pathways regulated by mitogen-activated/extracellular response kinase kinase kinase induce cell death. J Biol Chem. 1996 Feb 9;271(6):3229–3237. doi: 10.1074/jbc.271.6.3229. [DOI] [PubMed] [Google Scholar]
  24. Keroack M., Fields B. N. Viral shedding and transmission between hosts determined by reovirus L2 gene. Science. 1986 Jun 27;232(4758):1635–1638. doi: 10.1126/science.3012780. [DOI] [PubMed] [Google Scholar]
  25. Kudo H., Graham A. F. Selective inhibition of reovirus induced RNA in L cells. Biochem Biophys Res Commun. 1966 Jul 20;24(2):150–155. doi: 10.1016/0006-291x(66)90711-x. [DOI] [PubMed] [Google Scholar]
  26. Lee S., Christakos S., Small M. B. Apoptosis and signal transduction: clues to a molecular mechanism. Curr Opin Cell Biol. 1993 Apr;5(2):286–291. doi: 10.1016/0955-0674(93)90118-a. [DOI] [PubMed] [Google Scholar]
  27. Lucia-Jandris P., Hooper J. W., Fields B. N. Reovirus M2 gene is associated with chromium release from mouse L cells. J Virol. 1993 Sep;67(9):5339–5345. doi: 10.1128/jvi.67.9.5339-5345.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Meikrantz W., Schlegel R. Apoptosis and the cell cycle. J Cell Biochem. 1995 Jun;58(2):160–174. doi: 10.1002/jcb.240580205. [DOI] [PubMed] [Google Scholar]
  29. Mizumoto K., Rothman R. J., Farber J. L. Programmed cell death (apoptosis) of mouse fibroblasts is induced by the topoisomerase II inhibitor etoposide. Mol Pharmacol. 1994 Nov;46(5):890–895. [PubMed] [Google Scholar]
  30. Montgomery L. B., Kao C. Y., Verdin E., Cahill C., Maratos-Flier E. Infection of a polarized epithelial cell line with wild-type reovirus leads to virus persistence and altered cellular function. J Gen Virol. 1991 Dec;72(Pt 12):2939–2946. doi: 10.1099/0022-1317-72-12-2939. [DOI] [PubMed] [Google Scholar]
  31. Munemitsu S. M., Samuel C. E. Biosynthesis of reovirus-specified polypeptides. Multiplication rate but not yield of reovirus serotypes 1 and 3 correlates with the level of virus-mediated inhibition of cellular protein synthesis. Virology. 1984 Jul 15;136(1):133–143. doi: 10.1016/0042-6822(84)90254-x. [DOI] [PubMed] [Google Scholar]
  32. Nibert M. L., Fields B. N. A carboxy-terminal fragment of protein mu 1/mu 1C is present in infectious subvirion particles of mammalian reoviruses and is proposed to have a role in penetration. J Virol. 1992 Nov;66(11):6408–6418. doi: 10.1128/jvi.66.11.6408-6418.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Obeid L. M., Hannun Y. A. Ceramide: a stress signal and mediator of growth suppression and apoptosis. J Cell Biochem. 1995 Jun;58(2):191–198. doi: 10.1002/jcb.240580208. [DOI] [PubMed] [Google Scholar]
  34. Pushkareva M., Obeid L. M., Hannun Y. A. Ceramide: an endogenous regulator of apoptosis and growth suppression. Immunol Today. 1995 Jun;16(6):294–297. doi: 10.1016/0167-5699(95)80184-7. [DOI] [PubMed] [Google Scholar]
  35. ROSEN L., ABINANTI F. R., HOVIS J. F. Further observations on the natural infection of cattle with reoviruses. Am J Hyg. 1963 Jan;77:38–48. doi: 10.1093/oxfordjournals.aje.a120294. [DOI] [PubMed] [Google Scholar]
  36. ROSEN L., HOVIS J. F., MASTROTA F. M., BELL J. A., HUEBNER R. J. Observations on a newly recognized virus (Abney) of the reovirus family. Am J Hyg. 1960 Mar;71:258–265. doi: 10.1093/oxfordjournals.aje.a120109. [DOI] [PubMed] [Google Scholar]
  37. Roner M. R., Cox D. C. Cellular integrity is required for inhibition of initiation of cellular DNA synthesis by reovirus type 3. J Virol. 1985 Feb;53(2):350–359. doi: 10.1128/jvi.53.2.350-359.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rubin D. H., Fields B. N. Molecular basis of reovirus virulence. Role of the M2 gene. J Exp Med. 1980 Oct 1;152(4):853–868. doi: 10.1084/jem.152.4.853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Saragovi H. U., Bhandoola A., Lemercier M. M., Akbar G. K., Greene M. I. A receptor that subserves reovirus binding can inhibit lymphocyte proliferation triggered by mitogenic signals. DNA Cell Biol. 1995 Aug;14(8):653–664. doi: 10.1089/dna.1995.14.653. [DOI] [PubMed] [Google Scholar]
  40. Sawai H., Okazaki T., Yamamoto H., Okano H., Takeda Y., Tashima M., Sawada H., Okuma M., Ishikura H., Umehara H. Requirement of AP-1 for ceramide-induced apoptosis in human leukemia HL-60 cells. J Biol Chem. 1995 Nov 10;270(45):27326–27331. doi: 10.1074/jbc.270.45.27326. [DOI] [PubMed] [Google Scholar]
  41. Sharpe A. H., Chen L. B., Fields B. N. The interaction of mammalian reoviruses with the cytoskeleton of monkey kidney CV-1 cells. Virology. 1982 Jul 30;120(2):399–411. doi: 10.1016/0042-6822(82)90040-x. [DOI] [PubMed] [Google Scholar]
  42. Sharpe A. H., Fields B. N. Reovirus inhibition of cellular DNA synthesis: role of the S1 gene. J Virol. 1981 Apr;38(1):389–392. doi: 10.1128/jvi.38.1.389-392.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sharpe A. H., Fields B. N. Reovirus inhibition of cellular RNA and protein synthesis: role of the S4 gene. Virology. 1982 Oct 30;122(2):381–391. doi: 10.1016/0042-6822(82)90237-9. [DOI] [PubMed] [Google Scholar]
  44. Shaw J. E., Cox D. C. Early inhibition of cellular DNA synthesis by high multiplicities of infectious and UV-inactivated Reovirus. J Virol. 1973 Oct;12(4):704–710. doi: 10.1128/jvi.12.4.704-710.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Sherry B., Fields B. N. The reovirus M1 gene, encoding a viral core protein, is associated with the myocarditic phenotype of a reovirus variant. J Virol. 1989 Nov;63(11):4850–4856. doi: 10.1128/jvi.63.11.4850-4856.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Strong J. E., Lee P. W. The v-erbB oncogene confers enhanced cellular susceptibility to reovirus infection. J Virol. 1996 Jan;70(1):612–616. doi: 10.1128/jvi.70.1.612-616.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Strong J. E., Tang D., Lee P. W. Evidence that the epidermal growth factor receptor on host cells confers reovirus infection efficiency. Virology. 1993 Nov;197(1):405–411. doi: 10.1006/viro.1993.1602. [DOI] [PubMed] [Google Scholar]
  48. Tosteson M. T., Nibert M. L., Fields B. N. Ion channels induced in lipid bilayers by subvirion particles of the nonenveloped mammalian reoviruses. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10549–10552. doi: 10.1073/pnas.90.22.10549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Tyler K. L., Bronson R. T., Byers K. B., Fields B. Molecular basis of viral neurotropism: experimental reovirus infection. Neurology. 1985 Jan;35(1):88–92. doi: 10.1212/wnl.35.1.88. [DOI] [PubMed] [Google Scholar]
  50. Tyler K. L., Squier M. K., Rodgers S. E., Schneider B. E., Oberhaus S. M., Grdina T. A., Cohen J. J., Dermody T. S. Differences in the capacity of reovirus strains to induce apoptosis are determined by the viral attachment protein sigma 1. J Virol. 1995 Nov;69(11):6972–6979. doi: 10.1128/jvi.69.11.6972-6979.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Ucker D. S. Death by suicide: one way to go in mammalian cellular development? New Biol. 1991 Feb;3(2):103–109. [PubMed] [Google Scholar]
  52. Verdin E. M., Maratos-Flier E., Carpentier J. L., Kahn C. R. Persistent infection with a nontransforming RNA virus leads to impaired growth factor receptors and response. J Cell Physiol. 1986 Sep;128(3):457–465. doi: 10.1002/jcp.1041280315. [DOI] [PubMed] [Google Scholar]
  53. Weiner H. L., Fields B. N. Neutralization of reovirus: the gene responsible for the neutralization antigen. J Exp Med. 1977 Nov 1;146(5):1305–1310. doi: 10.1084/jem.146.5.1305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Weiner H. L., Powers M. L., Fields B. N. Absolute linkage of virulence and central nervous system cell tropism of reoviruses to viral hemagglutinin. J Infect Dis. 1980 May;141(5):609–616. doi: 10.1093/infdis/141.5.609. [DOI] [PubMed] [Google Scholar]
  55. Wessner D. R., Fields B. N. Isolation and genetic characterization of ethanol-resistant reovirus mutants. J Virol. 1993 May;67(5):2442–2447. doi: 10.1128/jvi.67.5.2442-2447.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Wilson G. A., Morrison L. A., Fields B. N. Association of the reovirus S1 gene with serotype 3-induced biliary atresia in mice. J Virol. 1994 Oct;68(10):6458–6465. doi: 10.1128/jvi.68.10.6458-6465.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Xia Z., Dickens M., Raingeaud J., Davis R. J., Greenberg M. E. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995 Nov 24;270(5240):1326–1331. doi: 10.1126/science.270.5240.1326. [DOI] [PubMed] [Google Scholar]
  58. van der Geer P., Hunter T., Lindberg R. A. Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol. 1994;10:251–337. doi: 10.1146/annurev.cb.10.110194.001343. [DOI] [PubMed] [Google Scholar]

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