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:

Cooperative and redundant effects of STAT5 and Ras signaling in BCR/ABL transformed hematopoietic cells

Oncogene volume 20, pages 5826–5835 (2001)Cite this article

Abstract

The Akt, Ras and STAT5 signaling pathways have each been linked to transformation of hematopoietic cells by BCR/ABL. However the relative contributions of these signaling pathways to BCR/ABL mediated cytokine-independent survival, proliferation and resistance to DNA damage-induced apoptosis have not been systematically defined. Here we report that activation of either Akt, Ras or STAT5 confers cytokine-independent survival to IL-3 dependent BaF3 cells. Ras or STAT5, but not Akt, also drives cytokine-independent proliferation and imparts sustained resistance to DNA damage-induced apoptosis. We also show that dominant negative (DN) inhibition of STAT5, but not Ras or Akt, significantly reduces resistance to DNA damage-induced apoptosis in BCR/ABL transformed BaF3 cells. Whereas inhibition of STAT5 or Ras alone does not compromise cytokine-independent proliferation of BaF3-BCR/ABL cells, simultaneous blockade of both STAT5 and Ras reduces proliferation and maximally sensitizes BaF3-BCR/ABL cells to DNA damage induced by γ-irradiation, suggesting a cooperative role for these two signaling pathways in BCR/ABL transformation. The anti-apoptotic properties of BCR/ABL can be partly explained by an increase in the expression of Pim-1 and Bcl-XL, as ectopic expression of these STAT5 target genes imparts both cytokine-independent survival and partial γ-radiation resistance. These data illustrate both cooperative and redundant effects of STAT5 and Ras signaling in BCR/ABL transformed cells, with STAT5 playing a dominant role in resistance to DNA damage-induced apoptosis.

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
Figure 7
Figure 8

Similar content being viewed by others

Abbreviations

EMSA:

electromobility shift assay

IL-3:

interleukin 3

DN:

dominant negative

CA:

constitutively active

References

  • Ahmed NN, Grimes HL, Bellacosa A, Chan TO, Tsichlis PN . 1997 Proc. Natl. Acad. Sci. USA 94: 3627–3632

  • Amarante-Mendes GP, McGahon AJ, Nishioka WK, Afar DE, Witte ON, Green DR . 1998 Oncogene 16: 1383–1390

  • Amos TA, Lewis JL, Grand FH, Gooding RP, Goldman JM, Gordon MY . 1995 Br. J. Haematol. 91: 387–393

  • Bedi A, Barber JP, Bedi GC, el-Deiry WS, Sidransky D, Vala MS, Akhtar AJ, Hilton J, Jones RJ . 1995 Blood 86: 1148–1158

  • Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ . 1994 Blood 83: 2038–2044

  • Ben-Neriah Y, Daley GQ, Mes-Masson AM, Witte ON, Baltimore D . 1986 Science 233: 212–214

  • Cambier N, Chopra R, Strasser A, Metcalf D, Elefanty AG . 1998 Oncogene 16: 335–348

  • Cortez D, Stoica G, Pierce JH, Pendergast AM . 1996 Oncogene 13: 2589–2594

  • Daley GQ, Baltimore D . 1988 Proc. Natl. Acad. Sci. USA 85: 9312–9316

  • Daley GQ, Van Etten RA, Baltimore D . 1990 Science 247: 824–830

  • Darnell Jr JE . 1997 Science 277: 1630–1635

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME . 1997 Cell 91: 231–241

  • Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB . 1996 Nat. Med. 2: 561–566

  • Dubrez L, Eymin B, Sordet O, Droin N, Turhan AG, Solary E . 1998 Blood 91: 2415–2422

  • Goga A, McLaughlin J, Afar DE, Saffran DC, Witte ON . 1995 Cell 82: 981–988

  • Horita M, Andreu EJ, Benito A, Arbona C, Sanz C, Benet I, Prosper F, Fernandez-Luna JL . 2000 J. Exp. Med. 191: 977–984

  • Ihle JN, Thierfelder W, Teglund S, Stravapodis D, Wang D, Feng J, Parganas E . 1998 Ann. NY Acad. Sci. 865: 1–9

  • Ilaria Jr RL, Van Etten RA . 1996 J. Biol. Chem. 271: 31704–31710

  • Janssen JW, Steenvoorden AC, Lyons J, Anger B, Bohlke JU, Bos JL, Seliger H, Bartram CR . 1987 Proc. Natl. Acad. Sci. USA 84: 9228–9232

  • Jiang X, Lopez A, Holyoake T, Eaves A, Eaves C . 1999 Proc. Natl. Acad. Sci. USA 96: 12804–12809

  • Klingmuller U, Bergelson S, Hsiao JG, Lodish HF . 1996 Proc. Natl. Acad. Sci. USA 93: 8324–8328

  • Li S, Ilaria Jr RL, Million RP, Daley GQ, Van Etten RA . 1999 J. Exp. Med. 189: 1399–1412

  • Lilly M, Kraft A . 1997 Cancer Res. 57: 5348–5355

  • Lugo TG, Pendergast AM, Muller AJ, Witte ON . 1990 Science 247: 1079–1082

  • Mandanas RA, Leibowitz DS, Gharehbaghi K, Tauchi T, Burgess GS, Miyazawa K, Jayaram HN, Boswell HS . 1993 Blood 82: 1838–1847

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

  • Onishi M, Nosaka T, Misawa K, Mui AL, Gorman D, McMahon M, Miyajima A, Kitamura T . 1998 Mol. Cell. Biol. 18: 3871–3879

  • Palacios R, Steinmetz M . 1985 Cell 41: 727–734

  • Pendergast AM, Quilliam LA, Cripe LD, Bassing CH, Dai Z, Li N, Batzer A, Rabun KM, Der CJ, Schlessinger J, Gishizky ML . 1993 Cell 75: 175–185

  • Peters DG, Hoover RR, Gerlach MJ, Koh EY, Zhang H, Choe K, Kirschmeier P, Bishop WR, Daley GQ . 2001 Blood 97: 1404–1412

  • Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci PG, Arlinghaus R, Pawson T . 1994 EMBO J. 13: 764–773

  • Quelle FW, Wang D, Nosaka T, Thierfelder WE, Stravopodis D, Weinstein Y, Ihle JN . 1996 Mol. Cell. Biol. 16: 1622–1631

  • Rebollo A, Martinez AC . 1999 Blood 94: 2971–2980

  • Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin Jr AS . 1998 Genes Dev. 12: 968–981

  • Rosa Santos SC, Dumon S, Mayeux P, Gisselbrecht S, Gouilleux F . 2000 Oncogene 19: 1164–1172

  • Sanchez-Garcia I, Grutz G . 1995 Proc. Natl. Acad. Sci. USA 92: 5287–5291

  • Sassone-Corsi P, Der CJ, Verma IM . 1989 Mol. Cell. Biol. 9: 3174–3183

  • Schwaller J, Parganas E, Wang D, Cain D, Aster JC, Williams IR, Lee CK, Gerthner R, Kitamura T, Frantsve J, Anastasiadou E, Loh ML, Levy DE, Ihle JN, Gilliland DG . 2000 Mol. Cell. 6: 693–704

  • Sexl V, Piekorz R, Moriggl R, Rohrer J, Brown MP, Bunting KD, Rothammer K, Roussel MF, Ihle JN . 2000 Blood 96: 2277–2283

  • Sillaber C, Gesbert F, Frank DA, Sattler M, Griffin JD . 2000 Blood 95: 2118–2125

  • Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan TO, Wasik MA, Tsichlis PN, Calabretta B . 1997 EMBO J. 16: 6151–6161

  • Skorski T, Nieborowska-Skorska M, Szczylik C, Kanakaraj P, Perrotti D, Zon G, Gewirtz A, Perussia B, Calabretta B . 1995 Cancer Res. 55: 2275–2278

  • Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF . 1999 Cell 98: 181–191

  • Terada K, Kaziro Y, Satoh T . 1995 J. Biol. Chem. 270: 27880–27886

  • Wang D, Stravopodis D, Teglund S, Kitazawa J, Ihle JN . 1996 Mol. Cell. Biol. 16: 6141–6148

  • Wang Q, Somwar R, Bilan PJ, Liu Z, Jin J, Woodgett JR, Klip A . 1999 Mol. Cell. Biol. 19: 4008–4018

  • Wilson-Rawls J, Xie S, Liu J, Laneuville P, Arlinghaus RB . 1996 Cancer Res. 56: 3426–3430

Download references

Acknowledgements

Supported by a grant from the Schering-Plough Research Institute and grants from the NCI (CA76418 and CA86991). GQ Daley is a recipient of the Burroughs Wellcome Career Development Award and is the Birnbaum Scholar of the Leukemia and Lymphoma Society of America.

Author information

Authors and Affiliations

  1. Whitehead Institute, 9 Cambridge Center, Cambridge, MA 02142, Massachusetts, USA

    Russell R Hoover, Melissa J Gerlach, Eugene Y Koh & George Q Daley

Authors
  1. Russell R Hoover
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Melissa J Gerlach
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eugene Y Koh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. George Q Daley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George Q Daley.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoover, R., Gerlach, M., Koh, E. et al. Cooperative and redundant effects of STAT5 and Ras signaling in BCR/ABL transformed hematopoietic cells. Oncogene 20, 5826–5835 (2001). https://doi.org/10.1038/sj.onc.1204549

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204549

Keywords

This article is cited by

Search

Advanced search

Quick links