Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Oncogene cooperativity in Friend erythroleukemia: erythropoietin receptor activation by the env gene of SFFV leads to transcriptional upregulation of PU.1, independent of SFFV proviral insertion

Abstract

Cancer is a multi-step, multi-genetic event. Whether oncogenic mutations cooperate with one another to transform cells and how is not well understood. The Friend murine retroviral erythroleukemia model involves mitogenic activation of the erythropoietin receptor (EpoR) by the virus env gene (F-gp55), aberrant over-expression of the transcription factor PU.1, and inactivating mutations in p53. In this report we demonstrate that concurrent expression of F-gp55 and PU.1 in erythroid target cells, in vivo, cooperate to accelerate erythroleukemia induction. Early in the disease, prior to the detection of clonal leukemic cells, activation of the EpoR by F-gp55, but not erythropoietin, resulted in transcriptional upregulation of PU.1 through a trans regulatory mechanism. This could occur in the absence of an integrated provirus within the PU.1 gene locus. The regulation of PU.1 transcription in established erythroleukemia cell lines differed depending upon the level of PU.1 protein present. Our results suggest that the action of F-gp55 contributes to both early and late stages of Friend erythroleukemia and that persistence of F-gp55 expression may be required not only to initiate erythroleukemia but to also maintain erythroleukemia following Friend virus infection.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Barnache S, Wendling F, Lacombe C, Denis N, Titeux M, Vainchecker W, Moreaeu-Gachelin F . 1998 Oncogene 16: 2989–2995

  • Beckman DL, Lin LL, Quinones ME, Longmore GD . 1999 Blood 94: 2667–2675

  • Ben-David Y, Bernstein A . 1991 Cell 66: 831–834

  • Bestwick RK, Kozak SL, Kabat D . 1988 Proc. Natl. Acad. Sci. (USA) 85: 5404–5408

  • Chen H, Ray-Gallet D, Zhang P, Hetherington CJ, Gonzalez DA, Zhang D-E, Moreau-Gachelin F, Tenen DG . 1995 Oncogene 11: 1549–1560

  • Chen H, Zhang P, Radomska HS, Hetherington C, Zhang D-E, Tenen DG . 1996 J. Biol. Chem. 271: 15743–15752

  • Choi S-Y, Faller DV . 1995 J. Virol. 69: 7054–7060

  • Elnitski L, Hardison R . 1999 Blood Cells 25: 299–304

  • Fearon ER, Vogelstein B . 1990 Cell 61: 759–767

  • Ghosh SK, Faller DV . 1999 J. Virol. 73: 4931–4940

  • Hoatlin ME, Kabat D . 1995 Trends in Microbiology 3: 51–57

  • Howard JC, Yousefi S, Cheong G, Bernstein A, Ben-David Y . 1993 Oncogene 8: 2721–2729

  • Hromas R, Orazi A, Meiman RS, Maki R, Van Beveran C, Moore J, Klemscz M . 1993 Blood 82: 2998–3004

  • Jonkers J, Berns A . 1996 Biochem. Biophys. Acta 1287: 29–57

  • Kelley LL, Hicks GG, Hsieh FF, Prasher JM, Green WF, Miller MD, Eide EJ, Ruley HE . 1998 Oncogene 17: 1119–1130

  • Li J-P, Bestwick RK, Spiro C, Kabat D . 1987 J. Virol. 61: 2782–2792

  • Li J-P, D'Andrea A, Lodish H, Baltimore D . 1990 Nature 343: 762–764

  • Li JP, Hu HO, Niu QT, Fang C . 1995 J. Virol. 69: 1714–1719

  • Longmore GD, Lodish HF . 1991 Cell 67: 1089–1102

  • Longmore GD, Pharr PN, Lodish HF . 1994 Mol. Cell. Biol. 14: 2266–2277

  • Mager D, Mak TW, Bernstein A . 1981 Proc. Natl. Acad. Sci. USA 78: 1703–1707

  • Moreau-Gachelin F, Ray D, Mattei M-G, Tambourin P, Tavitian A . 1989 Oncogene 4: 1449–1456

  • Moreau-Gachelin F, Tavatian A, Tambourin P . 1988 Nature 331: 277–280

  • Moreau-Gachelin F, Wendling F, Molina T, Denis N, Titeux M, Grimber G, Briand P, Vainchenker W, Tavitian A . 1996 Mol. Cell. Biol. 16: 2453–2463

  • Mowat M, Cheng A, Kimura N, Bernstein A, Benchimol S . 1985 Nature 314: 633–636

  • Muszynski KM, Thompson D, Hanson C, Lyons R, Spadaccini A, Ruscetti SK . 2000 J. Virology 74: 8444–8451

  • Muszynski KW, Ohashi T, Hanson C, Ruscetti SK . 1998 J. Virology 72: 919–925

  • Nishigaki K, Hanson C, Ohashi T, Thompson D, Muszynski K, Ruscetti SK . 2000 J. Virology 74: 3037–3045

  • Paul R, Scheutze S, Kozak SL, Kozak CA, Kabat D . 1991 J. Virol. 65: 464–467

  • Paul R, Schuetze S, Kozak S, Kabat D . 1989 J. Virol. 63: 4958–4961

  • Pereira R, Raingeaud J, Pironin M, Ghysdael J, Tran Quang C . 2000 Oncogene 19: 5106–5110

  • Persons DA, Paulson RF, Loyd MR, Herley MT, Bodner SM, Bernstein A, Correll PH, Ney PA . 1999 Nature Genetics 23: 159–165

  • Rekhtman N, Radparvar F, Evans T, Skoultchi AI . 1999 Genes Dev. 13: 1398–1411

  • Rosen CA, Sodroski JG, Kettman R, Burny A, Haseltin WA . 1985 Science 227: 320–322

  • Ruscetti SK . 1999 Int. J. Biochem. Cell. Biol. 31: 1089–1109

  • Schuetze S, Paul R, Gliniak BC, Kabat D . 1992 Mol. Cell. Biol. 12: 2967–2975

  • Schuetze S, Stenberg PE, Kabat D . 1993 Mol. Cell. Biol. 13: 5670–5678

  • Sodroski JG, Rosen C, Haseltine W . 1984 Science 225: 381–385

  • Tarr K, Watowich SS, Longmore GD . 1997 J. Biol. Chem. 272: 9099–9107

  • Tran Quang C, Wessely O, Pironin M, Beug H, Ghysdael J . 1997 EMBO J. 16: 5639–5653

  • Vannucchi AM, Paoletti F, Linari S, Cellai C, Caporale R, Ferrini P, Sanchez M, Migliaccio G, Migliaccio AR . 2000 Blood 95: 2559–2568

  • Weinberg RA . 1989 Oncogenes and the molecular origins of cancer R.A. Weinberg Cold Spring Harbor, Cold Spring Harbor Laboratory Press 307–327

    Google Scholar 

  • Wolff L, Ruscetti S . 1985 Science 228: 1549–1554

  • Yamada T, Kondoh N, Matsumoto M, Yoshida M, Maekawa A, Oikawa T . 1997 Blood 89: 1383–1393

  • Yoshimura A, Ohkubo T, Kiguchi T, Jenkins N, Gilbert DJ, Copeland NG, Hara T, Miyajima A . 1995 EMBO J. 14: 2816–2826

  • Zhang P, Behre G, Pan J, Iwama A, Wara-aswapati N, Radomska HS, Auron PE, Tenen DG, Sun Z . 1999 Proc. Natl. Acad. Sci. USA 96: 8705–8710

Download references

Acknowledgements

We would like to thank Dr Dan Tenen (Harvard Medical School, Boston MA, USA) for generously providing mouse PU.1 promoter luciferase plasmids, and helpful comments. Drs J Ghysdael and S Ruscetti for helpful comments. Dr T Yamada, Sasaki Institute, Tokyo for providing us with MEL-B8/3 cells. This work was supported by the NIH (R01 CA77447) and the Gillson Longenbaugh foundation (to SSW), and from the Association for International Cancer Research, the American Heart Association (9940116N), the Edward Mallinckrodt Jr. Foundation, and the NIH (RO1 CA75315) (to GD Longmore). GD Longmore is an Established Investigator of the American Heart Association.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gregory D Longmore.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Afrikanova, I., Yeh, E., Bartos, D. et al. Oncogene cooperativity in Friend erythroleukemia: erythropoietin receptor activation by the env gene of SFFV leads to transcriptional upregulation of PU.1, independent of SFFV proviral insertion. Oncogene 21, 1272–1284 (2002). https://doi.org/10.1038/sj.onc.1205183

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205183

Keywords

This article is cited by

Search

Quick links