1887

Abstract

Mouse mammary tumor virus (MMTV) is a complex betaretrovirus, which utilizes a Rev-like auxiliary protein Rem to export the unspliced viral RNA from the nucleus. MMTV mRNA appears to be exported via a distinct, Rem-independent, mechanism. Here, we analysed the effect of an extensively folded region coinciding with the 5′ leader sequence on gene expression. We found that the presence of the 5′ leader stimulates expression of the envelope protein. Enhanced Env production was accompanied by increased cytoplasmic levels of mRNA. The 5′ leader promotes nucleocytoplasmic translocation and increases stability of mRNA. The region responsible for this effect was mapped to the distal part of the 5′ leader. Furthermore, the 5′ leader inserted in the sense orientation into a heterologous luciferase expression construct increased luciferase activity.

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2012-02-01
2019-10-19
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References

  1. Aragón T. , van Anken E. , Pincus D. , Serafimova I. M. , Korennykh A. V. , Rubio C. A. , Walter P. . ( 2009; ). Messenger RNA targeting to endoplasmic reticulum stress signalling sites. . Nature 457:, 736–740. [CrossRef] [PubMed]
    [Google Scholar]
  2. Blissenbach M. , Grewe B. , Hoffmann B. , Brandt S. , Uberla K. . ( 2010; ). Nuclear RNA export and packaging functions of HIV-1 Rev revisited. . J Virol 84:, 6598–6604. [CrossRef] [PubMed]
    [Google Scholar]
  3. Bolinger C. , Boris-Lawrie K. . ( 2009; ). Mechanisms employed by retroviruses to exploit host factors for translational control of a complicated proteome. . Retrovirology 6:, 8.[PubMed] [CrossRef]
    [Google Scholar]
  4. Bolinger C. , Yilmaz A. , Hartman T. R. , Kovacic M. B. , Fernandez S. , Ye J. , Forget M. , Green P. L. , Boris-Lawrie K. . ( 2007; ). RNA helicase A interacts with divergent lymphotropic retroviruses and promotes translation of human T-cell leukemia virus type 1. . Nucleic Acids Res 35:, 2629–2642. [CrossRef] [PubMed]
    [Google Scholar]
  5. Bray M. , Prasad S. , Dubay J. W. , Hunter E. , Jeang K. T. , Rekosh D. , Hammarskjöld M. L. . ( 1994; ). A small element from the Mason-Pfizer monkey virus genome makes human immunodeficiency virus type 1 expression and replication Rev-independent. . Proc Natl Acad Sci U S A 91:, 1256–1260. [CrossRef] [PubMed]
    [Google Scholar]
  6. Butsch M. , Hull S. , Wang Y. , Roberts T. M. , Boris-Lawrie K. . ( 1999; ). The 5′ RNA terminus of spleen necrosis virus contains a novel posttranscriptional control element that facilitates human immunodeficiency virus Rev/RRE-independent Gag production. . J Virol 73:, 4847–4855.[PubMed]
    [Google Scholar]
  7. Dodson R. E. , Shapiro D. J. . ( 2002; ). Regulation of pathways of mRNA destabilization and stabilization. . Prog Nucleic Acid Res Mol Biol 72:, 129–164. [CrossRef] [PubMed]
    [Google Scholar]
  8. Emerman M. , Vazeux R. , Peden K. . ( 1989; ). The rev gene product of the human immunodeficiency virus affects envelope-specific RNA localization. . Cell 57:, 1155–1165. [CrossRef] [PubMed]
    [Google Scholar]
  9. Felber B. K. , Hadzopoulou-Cladaras M. , Cladaras C. , Copeland T. , Pavlakis G. N. . ( 1989; ). rev protein of human immunodeficiency virus type 1 affects the stability and transport of the viral mRNA. . Proc Natl Acad Sci U S A 86:, 1495–1499. [CrossRef] [PubMed]
    [Google Scholar]
  10. Fornerod M. , Ohno M. , Yoshida M. , Mattaj I. W. . ( 1997; ). CRM1 is an export receptor for leucine-rich nuclear export signals. . Cell 90:, 1051–1060. [CrossRef] [PubMed]
    [Google Scholar]
  11. Fukuda M. , Asano S. , Nakamura T. , Adachi M. , Yoshida M. , Yanagida M. , Nishida E. . ( 1997; ). CRM1 is responsible for intracellular transport mediated by the nuclear export signal. . Nature 390:, 308–311. [CrossRef] [PubMed]
    [Google Scholar]
  12. Golovkina T. V. , Dzuris J. , van den Hoogen B. , Jaffe A. B. , Wright P. C. , Cofer S. M. , Ross S. R. . ( 1998; ). A novel membrane protein is a mouse mammary tumor virus receptor. . J Virol 72:, 3066–3071.[PubMed]
    [Google Scholar]
  13. Günzburg W. H. , Salmons B. . ( 1986; ). Mouse mammary tumor virus mediated transfer and expression of neomycin resistance to infected cultured cells. . Virology 155:, 236–248. [CrossRef] [PubMed]
    [Google Scholar]
  14. Hartman T. R. , Qian S. , Bolinger C. , Fernandez S. , Schoenberg D. R. , Boris-Lawrie K. . ( 2006; ). RNA helicase A is necessary for translation of selected messenger RNAs. . Nat Struct Mol Biol 13:, 509–516. [CrossRef] [PubMed]
    [Google Scholar]
  15. Heinkelein M. , Thurow J. , Dressler M. , Imrich H. , Neumann-Haefelin D. , McClure M. O. , Rethwilm A. . ( 2000; ). Complex effects of deletions in the 5′ untranslated region of primate foamy virus on viral gene expression and RNA packaging. . J Virol 74:, 3141–3148. [CrossRef] [PubMed]
    [Google Scholar]
  16. Hofacre A. , Nitta T. , Fan H. . ( 2009; ). Jaagsiekte sheep retrovirus encodes a regulatory factor, Rej, required for synthesis of Gag protein. . J Virol 83:, 12483–12498. [CrossRef] [PubMed]
    [Google Scholar]
  17. Howard D. K. , Colcher D. , Teramoto Y. A. , Young J. M. , Schlom J. . ( 1977; ). Characterization of mouse mammary tumor viruses propagated in heterologous cells. . Cancer Res 37:, 2696–2704.[PubMed]
    [Google Scholar]
  18. Hüttelmaier S. , Zenklusen D. , Lederer M. , Dictenberg J. , Lorenz M. , Meng X. , Bassell G. J. , Condeelis J. , Singer R. H. . ( 2005; ). Spatial regulation of beta-actin translation by Src-dependent phosphorylation of ZBP1. . Nature 438:, 512–515. [CrossRef] [PubMed]
    [Google Scholar]
  19. Indik S. , Günzburg W. H. , Salmons B. , Rouault F. . ( 2005a; ). A novel, mouse mammary tumor virus encoded protein with Rev-like properties. . Virology 337:, 1–6. [CrossRef] [PubMed]
    [Google Scholar]
  20. Indik S. , Günzburg W. H. , Salmons B. , Rouault F. . ( 2005b; ). Mouse mammary tumor virus infects human cells. . Cancer Res 65:, 6651–6659. [CrossRef] [PubMed]
    [Google Scholar]
  21. Klein D. , Indraccolo S. , von Rombs K. , Amadori A. , Salmons B. , Günzburg W. H. . ( 1997; ). Rapid identification of viable retrovirus-transduced cells using the green fluorescent protein as a marker. . Gene Ther 4:, 1256–1260. [CrossRef] [PubMed]
    [Google Scholar]
  22. LeBlanc J. J. , Uddowla S. , Abraham B. , Clatterbuck S. , Beemon K. L. . ( 2007; ). Tap and Dbp5, but not Gag, are involved in DR-mediated nuclear export of unspliced Rous sarcoma virus RNA. . Virology 363:, 376–386. [CrossRef] [PubMed]
    [Google Scholar]
  23. Löwer R. , Tönjes R. R. , Korbmacher C. , Kurth R. , Löwer J. . ( 1995; ). Identification of a Rev-related protein by analysis of spliced transcripts of the human endogenous retroviruses HTDV/HERV-K. . J Virol 69:, 141–149.[PubMed]
    [Google Scholar]
  24. Malim M. H. , Hauber J. , Fenrick R. , Cullen B. R. . ( 1988; ). Immunodeficiency virus rev trans-activator modulates the expression of the viral regulatory genes. . Nature 335:, 181–183. [CrossRef] [PubMed]
    [Google Scholar]
  25. Malim M. H. , Hauber J. , Le S. Y. , Maizel J. V. , Cullen B. R. . ( 1989; ). The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA. . Nature 338:, 254–257. [CrossRef] [PubMed]
    [Google Scholar]
  26. Mertz J. A. , Simper M. S. , Lozano M. M. , Payne S. M. , Dudley J. P. . ( 2005; ). Mouse mammary tumor virus encodes a self-regulatory RNA export protein and is a complex retrovirus. . J Virol 79:, 14737–14747. [CrossRef] [PubMed]
    [Google Scholar]
  27. Müllner M. , Salmons B. , Günzburg W. H. , Indik S. . ( 2008; ). Identification of the Rem-responsive element of mouse mammary tumor virus. . Nucleic Acids Res 36:, 6284–6294. [CrossRef] [PubMed]
    [Google Scholar]
  28. Neville M. , Stutz F. , Lee L. , Davis L. I. , Rosbash M. . ( 1997; ). The importin-beta family member Crm1p bridges the interaction between Rev and the nuclear pore complex during nuclear export. . Curr Biol 7:, 767–775. [CrossRef] [PubMed]
    [Google Scholar]
  29. Nitta T. , Hofacre A. , Hull S. , Fan H. . ( 2009; ). Identification and mutational analysis of a Rej response element in Jaagsiekte sheep retrovirus RNA. . J Virol 83:, 12499–12511. [CrossRef] [PubMed]
    [Google Scholar]
  30. Ossareh-Nazari B. , Bachelerie F. , Dargemont C. . ( 1997; ). Evidence for a role of CRM1 in signal-mediated nuclear protein export. . Science 278:, 141–144. [CrossRef] [PubMed]
    [Google Scholar]
  31. Paca R. E. , Ogert R. A. , Hibbert C. S. , Izaurralde E. , Beemon K. L. . ( 2000; ). Rous sarcoma virus DR posttranscriptional elements use a novel RNA export pathway. . J Virol 74:, 9507–9514. [CrossRef] [PubMed]
    [Google Scholar]
  32. Pambalk K. , Hohenadl C. , Salmons B. , Günzburg W. H. , Renner M. . ( 2002; ). Specific packaging of spliced retroviral vector transcripts lacking the Psi-region. . Biochem Biophys Res Commun 293:, 239–246. [CrossRef] [PubMed]
    [Google Scholar]
  33. Roberts T. M. , Boris-Lawrie K. . ( 2000; ). The 5′ RNA terminus of spleen necrosis virus stimulates translation of nonviral mRNA. . J Virol 74:, 8111–8118. [CrossRef] [PubMed]
    [Google Scholar]
  34. Russell R. A. , Zeng Y. , Erlwein O. , Cullen B. R. , McClure M. O. . ( 2001; ). The R region found in the human foamy virus long terminal repeat is critical for both Gag and Pol protein expression. . J Virol 75:, 6817–6824. [CrossRef] [PubMed]
    [Google Scholar]
  35. Sinn P. L. , Burnight E. R. , Shen H. , Fan H. , McCray P. B. Jr . ( 2005; ). Inclusion of Jaagsiekte sheep retrovirus proviral elements markedly increases lentivirus vector pseudotyping efficiency. . Mol Ther 11:, 460–469. [CrossRef] [PubMed]
    [Google Scholar]
  36. Stade K. , Ford C. S. , Guthrie C. , Weis K. . ( 1997; ). Exportin 1 (Crm1p) is an essential nuclear export factor. . Cell 90:, 1041–1050. [CrossRef] [PubMed]
    [Google Scholar]
  37. Wang Y. , Jiang J. D. , Xu D. , Li Y. , Qu C. , Holland J. F. , Pogo B. G. . ( 2004; ). A mouse mammary tumor virus-like long terminal repeat superantigen in human breast cancer. . Cancer Res 64:, 4105–4111. [CrossRef] [PubMed]
    [Google Scholar]
  38. Xu L. , Shen Z. , Guo L. , Fodera B. , Keogh A. , Joplin R. , O’Donnell B. , Aitken J. , Carman W. . & other authors ( 2003; ). Does a betaretrovirus infection trigger primary biliary cirrhosis?. Proc Natl Acad Sci U S A 100:, 8454–8459. [CrossRef] [PubMed]
    [Google Scholar]
  39. Zolotukhin A. S. , Valentin A. , Pavlakis G. N. , Felber B. K. . ( 1994; ). Continuous propagation of RRE(-) and Rev(-)RRE(-) human immunodeficiency virus type 1 molecular clones containing a cis-acting element of simian retrovirus type 1 in human peripheral blood lymphocytes. . J Virol 68:, 7944–7952.[PubMed]
    [Google Scholar]
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