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 Article
  • Published:

Constitutive STAT5 activation specifically cooperates with the loss of p53 function in B-cell lymphomagenesis

Oncogene volume 25, pages 4573–4584 (2006)Cite this article

Abstract

Signal transducers and activator of transcription 5 (STAT5) A and B are transcriptional regulators that play a central role in cytokine signaling in the hematopoietic lineage and which are frequently activated in a persistent manner in human leukemia/lymphoma, as assessed by their constitutive tyrosine phosphorylation and DNA-binding activity. To study the intrinsic oncogenic properties of persistent STAT5 activation, we generated transgenic mice in which a constitutively activated point mutant of STAT5A, STAT5A(S711F), was expressed at physiological level in their lymphoid compartment. In this model, persistent STAT5 activation is weakly oncogenic, leading to the late emergence of clonal B-cell lymphoma/leukemia at a low incidence. In contrast, STAT5(S711F) was found to cooperate with the loss of function of the p53 tumor suppressor gene to both accelerate disease onset and to skew the large tumor spectrum that normally characterize p53-deficient mice to strongly favor B-cell lymphoma/leukemia. The emergence of STAT5A(S711F)-induced B-cell tumors is associated with the activation of STAT5 tyrosine phosphorylation and DNA-binding activity, indicating that activation of STAT5 oncogenic properties in transgenic STAT5A (TgSTAT5A) (S711F) mice involves the deregulation of STAT5 phosphorylation dynamics.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

  • Abraham N, Ma MC, Snow JW, Miners MJ, Herndier BG, Goldsmith MA . (2005). Oncogene 24: 5252–5257.

  • Aoki N, Matsuda T . (2000). J Biol Chem 275: 39718–39726.

  • Benekli M, Baer MR, Baumann H, Wetzler M . (2003). Blood 101: 2940–2954.

  • Bodrug SE, Warner BJ, Bath ML, Lindeman GJ, Harris AW, Adams JM . (1994). EMBO J 13: 2124–2130.

  • Bowman T, Garcia R, Turkson J, Jove R . (2000). Oncogene 19: 2474–2488.

  • Bromberg J . (2002). J Clin Invest 109: 1139–1142.

  • Bunting KD, Bradley HL, Hawley TS, Moriggl R, Sorrentino BP, Ihle JN . (2002). Blood 99: 479–487.

  • Burchill MA, Goetz CA, Prlic M, O'Neil JJ, Harmon IR, Bensinger SJ et al. (2003). J Immunol 171: 5853–5864.

  • Carlesso N, Frank DA, Griffin JD . (1996). J Exp Med 183: 811–820.

  • Carron C, Cormier F, Janin A, Lacronique V, Giovannini M, Daniel MT et al. (2000). Blood 95: 3891–3899.

  • Chen Y, Wen R, Yang S, Schuman J, Zhang EE, Yi T et al. (2003). J Biol Chem 278: 16520–16527.

  • Cui Y, Riedlinger G, Miyoshi K, Tang W, Li C, Deng CX et al. (2004). Mol Cell Biol 24: 8037–8047.

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery Jr CA, Butel JS et al. (1992). Nature 356: 215–221.

  • Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL . (1999). Genes Dev 13: 2658–2669.

  • Fleming HE, Milne CD, Paige CJ . (2004). J Immunol 173: 2542–2551.

  • Fritsche M, Mundt M, Merkle C, Jahne R, Groner B . (1998). Mol Cell Endocrinol 143: 143–154.

  • Goetz CA, Harmon IR, O'Neil J J, Burchill MA, Johanns TM, Farrar MA . (2005). J Immunol 174: 7753–7763.

  • Goetz CA, Harmon IR, O'Neil JJ, Burchill MA, Farrar MA . (2004). J Immunol 172: 4770–4778.

  • Hemann MT, Fridman JS, Zilfou JT, Hernando E, Paddison PJ, Cordon-Cardo C et al. (2003). Nat Genet 33: 396–400.

  • Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G et al. (2001). Nature 409: 349–354.

  • Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA . (1994). Nat Genet 7: 353–361.

  • James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al. (2005). Nature 434: 1144–1148.

  • Kang J, DiBenedetto B, Narayan K, Zhao H, Der SD, Chambers CA . (2004). J Immunol 173: 2307–2314.

  • Kelly J, Spolski R, Imada K, Bollenbacher J, Lee S, Leonard WJ . (2003a). J Immunol 170: 210–217.

  • Kelly JA, Spolski R, Kovanen PE, Suzuki T, Bollenbacher J, Pise-Masison CA et al. (2003b). J Exp Med 198: 79–89.

  • Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW . (2002). Gene 285: 1–24.

  • Krug U, Ganser A, Koeffler HP . (2002). Oncogene 21: 3475–3495.

  • Kuperwasser C, Hurlbut GD, Kittrell FS, Dickinson ES, Laucirica R, Medina D et al. (2000). Am J Pathol 157: 2151–2159.

  • Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffe M et al. (1997). Science 278: 1309–1312.

  • Lebigot I, Gardellin P, Lefebvre L, Beug H, Ghysdael J, Quang CT . (2003). Blood 102: 4555–4562.

  • Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ et al. (2005). Cancer Cell 7: 387–397.

  • Liu G, Parant JM, Lang G, Chau P, Chavez-Reyes A, El-Naggar AK et al. (2004). Nat Genet 36: 63–68.

  • Liu X, Robinson GW, Wagner KU, Garrett L, Wynshaw-Boris A, Hennighausen L . (1997). Genes Dev 11: 179–186.

  • Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C et al. (2000). Blood 96: 3907–3914.

  • Moriggl R, Sexl V, Kenner L, Duntsch C, Stangl K, Gingras S et al. (2005). Cancer Cell 7: 87–99.

  • Moriggl R, Sexl V, Piekorz R, Topham D, Ihle JN . (1999). Immunity 11: 225–230.

  • Nieborowska-Skorska M, Wasik MA, Slupianek A, Salomoni P, Kitamura T, Calabretta B et al. (1999). J Exp Med 189: 1229–1242.

  • Onishi M, Nosaka T, Misawa K, Mui AL, Gorman D, McMahon M et al. (1998). Mol Cell Biol 18: 3871–3879.

  • Reddy J, Shivapurkar N, Takahashi T, Parikh G, Stastny V, Echebiri C et al. (2005). Oncogene 24: 732–736.

  • Sambroock J, Fritisch E, Maniatis T . (1989). Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, New york.

    Google Scholar 

  • Schmitt CA, Fridman JS, Yang M, Baranov E, Hoffman RM, Lowe SW . (2002). Cancer Cell 1: 289–298.

  • Schmitt CA, McCurrach ME, de Stanchina E, Wallace-Brodeur RR, Lowe SW . (1999). Genes Dev 13: 2670–2677.

  • Schwaller J, Parganas E, Wang D, Cain D, Aster JC, Williams IR et al. (2000). Mol Cell 6: 693–704.

  • Sexl V, Piekorz R, Moriggl R, Rohrer J, Brown MP, Bunting KD et al. (2000). Blood 96: 2277–2283.

  • Shuai K, Liu B . (2003). Nat Rev Immunol 3: 900–911.

  • Snow JW, Abraham N, Ma MC, Abbey NW, Herndier B, Goldsmith MA . (2002). Blood 99: 95–101.

  • Sommer VH, Clemmensen OJ, Nielsen O, Wasik M, Lovato P, Brender C et al. (2004). Leukemia 18: 1288–1295.

  • Sternberg DW, Gilliland DG . (2004). J Clin Oncol 22: 361–371.

  • Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D et al. (1998). Cell 93: 841–850.

  • Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA et al. (1997). Proc Natl Acad Sci USA 94: 7239–7244.

  • Weber-Nordt RM, Egen C, Wehinger J, Ludwig W, Gouilleux-Gruart V, Mertelsmann R et al. (1996). Blood 88: 809–816.

Download references

Acknowledgements

We thank Maryvonne Williame for expert technical assistance; Josiane Ropers, Yveline Bourgeois, Christophe Alberti for mouse handling and the SEAT of CNRS for their help in generating transgenic animals; Dr Christine Tran Quang for critical reading of the manuscript and Dr Richard Morrigl for discussions. This work was supported by funds from Centre National de la Recherche Scientifique (CNRS); Institut Curie; Ligue Nationale contre le Cancer (Equipe labellisée la Ligue); Association for International Cancer Research (AICR) and European Union.

Author information

Authors and Affiliations

  1. Institut Curie, CNRS UMR146, Centre Universitaire, Orsay, France

    V Joliot, F Cormier, H Medyouf, H Alcalde & J Ghysdael

  2. UFR Biochimie, Université Paris 7, Paris, France

    V Joliot

Authors
  1. V Joliot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Cormier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Medyouf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Alcalde
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Ghysdael
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Ghysdael.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Joliot, V., Cormier, F., Medyouf, H. et al. Constitutive STAT5 activation specifically cooperates with the loss of p53 function in B-cell lymphomagenesis. Oncogene 25, 4573–4584 (2006). https://doi.org/10.1038/sj.onc.1209480

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209480

Keywords

This article is cited by

Search

Advanced search

Quick links