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