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. 1996 Jun;70(6):3659–3667. doi: 10.1128/jvi.70.6.3659-3667.1996

Identification of nuclear and cytoplasmic proteins that interact specifically with an AU-rich, cis-acting inhibitory sequence in the 3' untranslated region of human papillomavirus type 1 late mRNAs.

C Zhao 1, W Tan 1, M Sokolowski 1, S Schwartz 1
PMCID: PMC190241  PMID: 8648700

Abstract

Expression of human papillomavirus late genes encoding L1 and L2 capsid proteins is restricted to terminally differentiated epithelial cells. We have previously identified and characterized an AU-rich, cis-acting negative regulatory element in the 3' untranslated region of human papillomavirus type 1 late mRNAs. This element acts posttranscriptionally to reduce mRNA levels and the translation efficiency of mRNAs. The experiments reported here are a continuation of our previous work. We have used RNA gel shifts and UV cross-linking assays to identify cellular proteins that interact with the inhibitory RNA sequence of human papillomavirus type 1. RNA gel shift assays established that cellular proteins interact with the AU-rich sequence. The binding of nuclear proteins was inhibited by competition with poly(U), whereas the binding of cytoplasmic proteins was inhibited by competition with poly(U) and also by competition with poly(A) and poly(G). Two nuclear proteins and two cytoplasmic proteins that bind specifically to the AU-rich RNA sequence were identified by UV cross-linking. These proteins did not bind to the 3' untranslated region of human papillomavirus type 1 early mRNAs, which does not show inhibitory activity. The cellular proteins identified in our experiments may therefore be involved in the inhibition of human papillomavirus type 1 late gene expression in nondifferentiated epithelial cells.

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Selected References

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  1. Bickel M., Iwai Y., Pluznik D. H., Cohen R. B. Binding of sequence-specific proteins to the adenosine- plus uridine-rich sequences of the murine granulocyte/macrophage colony-stimulating factor mRNA. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10001–10005. doi: 10.1073/pnas.89.21.10001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bohjanen P. R., Petryniak B., June C. H., Thompson C. B., Lindsten T. AU RNA-binding factors differ in their binding specificities and affinities. J Biol Chem. 1992 Mar 25;267(9):6302–6309. [PubMed] [Google Scholar]
  3. Bohjanen P. R., Petryniak B., June C. H., Thompson C. B., Lindsten T. An inducible cytoplasmic factor (AU-B) binds selectively to AUUUA multimers in the 3' untranslated region of lymphokine mRNA. Mol Cell Biol. 1991 Jun;11(6):3288–3295. doi: 10.1128/mcb.11.6.3288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brewer G. An A + U-rich element RNA-binding factor regulates c-myc mRNA stability in vitro. Mol Cell Biol. 1991 May;11(5):2460–2466. doi: 10.1128/mcb.11.5.2460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Danos O., Katinka M., Yaniv M. Human papillomavirus 1a complete DNA sequence: a novel type of genome organization among papovaviridae. EMBO J. 1982;1(2):231–236. doi: 10.1002/j.1460-2075.1982.tb01152.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eng A. M., Jin Y. T., Matsuoka L. Y., Grgurich C. V., Robinson J., Armin A. Correlative studies of Verruca vulgaris by H & E, PAP immunostaining, and electronmicroscopy. J Cutan Pathol. 1985 Feb;12(1):46–54. doi: 10.1111/j.1600-0560.1985.tb00429.x. [DOI] [PubMed] [Google Scholar]
  8. Furth P. A., Baker C. C. An element in the bovine papillomavirus late 3' untranslated region reduces polyadenylated cytoplasmic RNA levels. J Virol. 1991 Nov;65(11):5806–5812. doi: 10.1128/jvi.65.11.5806-5812.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Furth P. A., Choe W. T., Rex J. H., Byrne J. C., Baker C. C. Sequences homologous to 5' splice sites are required for the inhibitory activity of papillomavirus late 3' untranslated regions. Mol Cell Biol. 1994 Aug;14(8):5278–5289. doi: 10.1128/mcb.14.8.5278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Galloway D. A., McDougall J. K. Human papillomaviruses and carcinomas. Adv Virus Res. 1989;37:125–171. doi: 10.1016/s0065-3527(08)60834-9. [DOI] [PubMed] [Google Scholar]
  11. Geck P., Medveczky M. M., Chou C. S., Brown A., Cus J., Medveczky P. G. Herpesvirus saimiri small RNA and interleukin-4 mRNA AUUUA repeats compete for sequence-specific factors including a novel 70K protein. J Gen Virol. 1994 Sep;75(Pt 9):2293–2301. doi: 10.1099/0022-1317-75-9-2293. [DOI] [PubMed] [Google Scholar]
  12. Gillis P., Malter J. S. The adenosine-uridine binding factor recognizes the AU-rich elements of cytokine, lymphokine, and oncogene mRNAs. J Biol Chem. 1991 Feb 15;266(5):3172–3177. [PubMed] [Google Scholar]
  13. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  14. Grussendorf E. I., zur Hausen H. Localization of viral DNA-replication in sections of human warts by nucleic acid hybridization with complementary RNA of human papilloma virus Type 1. Arch Dermatol Res. 1979 Feb 23;264(1):55–63. doi: 10.1007/BF00417279. [DOI] [PubMed] [Google Scholar]
  15. Jenson A. B., Rosenthal J. D., Olson C., Pass F., Lancaster W. D., Shah K. Immunologic relatedness of papillomaviruses from different species. J Natl Cancer Inst. 1980 Mar;64(3):495–500. [PubMed] [Google Scholar]
  16. Jeon S., Lambert P. F. Integration of human papillomavirus type 16 DNA into the human genome leads to increased stability of E6 and E7 mRNAs: implications for cervical carcinogenesis. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1654–1658. doi: 10.1073/pnas.92.5.1654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Keller W. No end yet to messenger RNA 3' processing! Cell. 1995 Jun 16;81(6):829–832. doi: 10.1016/0092-8674(95)90001-2. [DOI] [PubMed] [Google Scholar]
  18. Kennedy I. M., Haddow J. K., Clements J. B. A negative regulatory element in the human papillomavirus type 16 genome acts at the level of late mRNA stability. J Virol. 1991 Apr;65(4):2093–2097. doi: 10.1128/jvi.65.4.2093-2097.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kennedy I. M., Haddow J. K., Clements J. B. Analysis of human papillomavirus type 16 late mRNA 3' processing signals in vitro and in vivo. J Virol. 1990 Apr;64(4):1825–1829. doi: 10.1128/jvi.64.4.1825-1829.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Laimins L. A. The biology of human papillomaviruses: from warts to cancer. Infect Agents Dis. 1993 Apr;2(2):74–86. [PubMed] [Google Scholar]
  21. Lambert P. F. Papillomavirus DNA replication. J Virol. 1991 Jul;65(7):3417–3420. doi: 10.1128/jvi.65.7.3417-3420.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Laurent R., Kienzler J. L., Croissant O., Orth G. Two anatomoclinical types of warts with plantar localization: specific cytopathogenic effects of papillomavirus. Type I (HPV-1) and type 2 (HPV-2). Arch Dermatol Res. 1982;274(1-2):101–111. doi: 10.1007/BF00510364. [DOI] [PubMed] [Google Scholar]
  23. Malter J. S. Identification of an AUUUA-specific messenger RNA binding protein. Science. 1989 Nov 3;246(4930):664–666. doi: 10.1126/science.2814487. [DOI] [PubMed] [Google Scholar]
  24. Myer V. E., Lee S. I., Steitz J. A. Viral small nuclear ribonucleoproteins bind a protein implicated in messenger RNA destabilization. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1296–1300. doi: 10.1073/pnas.89.4.1296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Müller W. E., Slor H., Pfeifer K., Hühn P., Bek A., Orsulic S., Ushijima H., Schröder H. C. Association of AUUUA-binding protein with A+U-rich mRNA during nucleo-cytoplasmic transport. J Mol Biol. 1992 Aug 5;226(3):721–733. doi: 10.1016/0022-2836(92)90628-w. [DOI] [PubMed] [Google Scholar]
  26. Nakagawa J., Waldner H., Meyer-Monard S., Hofsteenge J., Jenö P., Moroni C. AUH, a gene encoding an AU-specific RNA binding protein with intrinsic enoyl-CoA hydratase activity. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2051–2055. doi: 10.1073/pnas.92.6.2051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Port J. D., Huang L. Y., Malbon C. C. Beta-adrenergic agonists that down-regulate receptor mRNA up-regulate a M(r) 35,000 protein(s) that selectively binds to beta-adrenergic receptor mRNAs. J Biol Chem. 1992 Nov 25;267(33):24103–24108. [PubMed] [Google Scholar]
  28. Rajagopalan L. E., Malter J. S. Modulation of granulocyte-macrophage colony-stimulating factor mRNA stability in vitro by the adenosine-uridine binding factor. J Biol Chem. 1994 Sep 30;269(39):23882–23888. [PubMed] [Google Scholar]
  29. Ross J. mRNA stability in mammalian cells. Microbiol Rev. 1995 Sep;59(3):423–450. doi: 10.1128/mr.59.3.423-450.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schwartz S., Campbell M., Nasioulas G., Harrison J., Felber B. K., Pavlakis G. N. Mutational inactivation of an inhibitory sequence in human immunodeficiency virus type 1 results in Rev-independent gag expression. J Virol. 1992 Dec;66(12):7176–7182. doi: 10.1128/jvi.66.12.7176-7182.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Seedorf K., Krämmer G., Dürst M., Suhai S., Röwekamp W. G. Human papillomavirus type 16 DNA sequence. Virology. 1985 Aug;145(1):181–185. doi: 10.1016/0042-6822(85)90214-4. [DOI] [PubMed] [Google Scholar]
  32. Stephens J. M., Carter B. Z., Pekala P. H., Malter J. S. Tumor necrosis factor alpha-induced glucose transporter (GLUT-1) mRNA stabilization in 3T3-L1 preadipocytes. Regulation by the adenosine-uridine binding factor. J Biol Chem. 1992 Apr 25;267(12):8336–8341. [PubMed] [Google Scholar]
  33. Tan W., Felber B. K., Zolotukhin A. S., Pavlakis G. N., Schwartz S. Efficient expression of the human papillomavirus type 16 L1 protein in epithelial cells by using Rev and the Rev-responsive element of human immunodeficiency virus or the cis-acting transactivation element of simian retrovirus type 1. J Virol. 1995 Sep;69(9):5607–5620. doi: 10.1128/jvi.69.9.5607-5620.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tan W., Schwartz S. The Rev protein of human immunodeficiency virus type 1 counteracts the effect of an AU-rich negative element in the human papillomavirus type 1 late 3' untranslated region. J Virol. 1995 May;69(5):2932–2945. doi: 10.1128/jvi.69.5.2932-2945.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Turek L. P. The structure, function, and regulation of papillomaviral genes in infection and cervical cancer. Adv Virus Res. 1994;44:305–356. doi: 10.1016/s0065-3527(08)60332-2. [DOI] [PubMed] [Google Scholar]
  36. Vakalopoulou E., Schaack J., Shenk T. A 32-kilodalton protein binds to AU-rich domains in the 3' untranslated regions of rapidly degraded mRNAs. Mol Cell Biol. 1991 Jun;11(6):3355–3364. doi: 10.1128/mcb.11.6.3355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wahle E. The end of the message: 3'-end processing leading to polyadenylated messenger RNA. Bioessays. 1992 Feb;14(2):113–118. doi: 10.1002/bies.950140208. [DOI] [PubMed] [Google Scholar]
  38. You Y., Chen C. Y., Shyu A. B. U-rich sequence-binding proteins (URBPs) interacting with a 20-nucleotide U-rich sequence in the 3' untranslated region of c-fos mRNA may be involved in the first step of c-fos mRNA degradation. Mol Cell Biol. 1992 Jul;12(7):2931–2940. doi: 10.1128/mcb.12.7.2931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Zhang W., Wagner B. J., Ehrenman K., Schaefer A. W., DeMaria C. T., Crater D., DeHaven K., Long L., Brewer G. Purification, characterization, and cDNA cloning of an AU-rich element RNA-binding protein, AUF1. Mol Cell Biol. 1993 Dec;13(12):7652–7665. doi: 10.1128/mcb.13.12.7652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. de Villiers E. M. Human pathogenic papillomavirus types: an update. Curr Top Microbiol Immunol. 1994;186:1–12. doi: 10.1007/978-3-642-78487-3_1. [DOI] [PubMed] [Google Scholar]

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