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  • Original Paper
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IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line

Abstract

Activation of the Jak/STAT pathway by cytokines has been shown to regulate differentiation, proliferation or apoptosis in hematopoeitic cells. Among the Stat proteins, STAT5 is activated by a broad range of cytokines. In order to study the role of STAT5 in hematopoietic cells, we stably expressed a dominant negative form of STAT5 (STAT5AΔ749) in the IL-3 dependent bone marrow derived Ba/F3 cell line. Ba/F3 cells expressing STAT5AΔ749 were found to be more sensitive to apoptosis than parental or control Ba/F3 cells after IL-3 withdrawal. Analysis of the expression of the cell death regulators, Bcl-2 and Bcl-x, revealed that the level of Bcl-x was lower in Ba/F3 cells expressing STAT5AΔ749 than in control cells. IL-3 regulation of Bcl-x expression at protein and mRNA levels was impaired in these cells while that of Bcl-2 expression was unaffected. We further demonstrated that the Bcl-x gene promoter contained a proximal STAT consensus sequence that bound STAT5. Transactivation of a Bcl-x gene promoter reporter construct by STAT5 was observed in Ba/F3 cells. Introduction of a mutation in the STAT binding site abolished this transactivation. These data indicate that Bcl-x is probably a STAT5 target gene. They also support the involvement of STAT5 in hematopoietic cell survival.

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References

  • Ahmed M, Dusanter-Fourt I, Bernard M, Mayeux P, Hawley RG, Bennardo T, Novault S, Bonnet ML, Gisselbrecht S, Varet and Turham AG. . 1998 Oncogene 16: 489–496.

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

  • Azam M, Erdjument-Bromage H, Kreider BL, Xia M, Quelle F, Basu R, Saris C, Tempst P, Ihle JN and Schindler C. . 1995 EMBO J. 14: 1402–1114.

  • Azam M, Lee C, Strehlow I and Schindler C. . 1997 Immunity 6: 691–701.

  • Broome HE, Dargan CM, Krajewski S and Reed JC. . 1995 J. Immunol. 155: 2311–2317.

  • Caldenhoven E, van Dijk TB, Solari R, Armstrong J, Raaijmakers JAM, Lammers JWJ, Koenderman L and de Groot RP. . 1996 J. Biol. Chem. 271: 13221–13227.

  • Chai SK, Nichols GL and Rothman P. . 1997 J. Immunol. 15: 4720–4728.

  • Chen Q, Turner J, Watson AJ and Dive C. . 1997 Oncogene 15: 2249–2254.

  • Chretien S, Varlet P, Verdier F, Gobert S, Cartron JP, Gisselbrecht S, Mayeux P and Lacombe C. . 1996 EMBO J. 15: 4174–4181.

  • Danial NN, Pernis A and Rothman PB. . 1995 Science 269: 1875–1877

  • Darnell Jr JE, Kerr IM and Stark GR. . 1994 Science 264: 1415–1421.

  • David M, Petricoin III E, Benjamin C, Pine R, Weber MJ and Larner AC. . 1995 Science 269: 1721–1723.

  • del Peso L, Gonzales-Garcia M, Page C, Herrera R and Nunez G. . 1997 Science 278: 687–689.

  • Feldman GM, Rosenthal LA, Liu X, Hayes MP, Wynshaw-Boris A, Leonard WJ, Hennighausen L and Finbloom DS. . 1997 Blood 90: 1768–1776.

  • Friedmann MC, Migone TS, Russell SM and Leonard WJ. . 1996 Proc. Natl. Acad. Sci. USA 93: 2077–2082.

  • Franke TF, Kaplan DR and Cantley LC. . 1997 Cell 88: 435–437.

  • Fujii H, Nakagawa Y, Schindler U, Kawahara A, Mori H, Gouilleux F, Groner B, Ihle JN, Minami Y, Miyazaki T and Tamiguchi T. . 1995 Proc. Natl. Acad. Sci. USA 92: 5482–5486.

  • Fujio Y, Kunisada K, Hirota H, Yamauchi-Takihara K and Kishimoto T. . 1997 J. Clin. Invest. 99: 2898–2905.

  • Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T, Nakajima K and Hirano T. . 1996 Immunity 5: 449–460.

  • Gobert S, Chretien S, Gouilleux F, Muller O, Pallard C, Dusanter-Fourt I, Groner B, Lacombe C, Gisselbrecht S and Mayeux P. . 1996 EMBO J. 15: 2434–2441.

  • Gouilleux F, Pallard C, Dusanter-Fourt I, Wakao H, Haldosen LA, Norstedt G, Levy D and Groner B. . 1995 EMBO J. 14: 2005–2013.

  • Gouilleux F, Wakao H, Mundt M and Groner B. . 1994 EMBO J. 13: 4361–4639.

  • Gouilleux-Gruart V, Gouilleux F, Desaint C, Claisse JF, Capioid JC, Delobel J, Weber-Nordt R, Dusanter-Fourt I, Dreyfus F, Groner B and Prin L. . 1996 Blood 87: 1692–1697.

  • Grillot DAM, Gonzales-Garcia M, Ekhterae D, Duan L, Inohana N, Ohta S, Seldin MF and Nunez G. . 1997 J. Immunol. 158: 4750–4757.

  • Heim MH, Kerr IM, Stark GR and Darnell Jr JE. . 1995 Science 267: 1347–1349.

  • Horvath CM, Wen Z and Darnell Jr JE. . 1995 Genes Dev. 9: 984–994.

  • Ihle JN. . 1996 Cell 84: 331–334.

  • Ito T, Deng X, Carr B and May WS. . 1997 J. Biol. Chem. 272: 11671–11673.

  • Iwatsuki K, Endo T, Misawa H, Yokouchi M, Matsumoto A, Ohtsubo M, Mori KJ and Yoshimura A. . 1997 J. Biol. Chem. 272: 8149–8152.

  • Kanzansky AV, Raught B, Lindsey SM, Wang YF and Rosen JM. . 1995 Mol. Endocrinol 9: 1598–1609.

  • Kinoshita T, Yokota T, Arai K and Miyajima A. . 1995a Oncogene 10: 2207–2212.

  • Kinoshita T, Yokota T, Arai K and Miyajima A. . 1995b EMBO J. 14: 266–275.

  • Kishimoto T, Taga T and Akira S. . 1994 Cell 76: 253–262.

  • Lecine P, Algarte M, Rameil P, Beadling C, Bucher P, Nabholz M and Imbert J. . 1996 Mol. Cell. Biol. 16: 6829–6840.

  • Leverrier Y, Thomas J, Perkins GR, Mangeney M, Collins MK and Marvel J. . 1997 Oncogene 14: 425–430.

  • Leverrier Y, Thomas J, Mathuie AL, Low W, Blanquier B and Marvel J. . 1999 Cell Death Differ. in press.

  • Liu X, Robinson GW, Gouilleux F, Groner B and Hennighausen L. . 1995 Proc. Natl. Acad. Sci. USA 92: 8831–8835.

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

  • Matsumoto A, Masuhara M, Mitsui K, Yokouchi M, Ohtsubo M, Misawa H, Miyajima A and Yoshimura A. . 1997 Blood 89: 3148–3154.

  • Meyer J, Jucker M, Ostertag W and Stocking C. . 1998 Blood 91: 1901–1908.

  • Moriggl R, Berchtold S, Freidrich K, Standke GJ, Kammer W, Heim M, Wissler M, Stocklin E, Gouilleux F and Groner B. . 1997 Mol. Cell. Biol. 17: 3663–3678.

  • Moriggl R, Gouilleux-Gruart V, Jahne R, Berchtold S, Gartmann C, Liu X, Hennighausen L, Sotiropoulos A, Groner B and Gouilleux F. . 1996 Mol. Cell. Biol. 16: 5691–5700.

  • Mui AL, Wakao H, Am OF, Harada N and Miyajima A. . 1995 EMBO J. 14: 1166–1175.

  • Mui AL, Wakao H, Kinoshita T, Kitamura T and Miyajima A. . 1996 EMBO J. 15: 2425–2433.

  • Pallard C, Gouilleux F, Benit L, Cocault L, Souyri M, Levy D, Groner B, Gisselbrecht S and Dusanter-Fourt I. . 1995a EMBO J. 14: 2847–2856.

  • Pallard C, Gouilleux F, Charon M, Groner B, Gisselbrecht S and Dusanter-Fourt I. . 1995b J. Biol. Chem. 270: 15942–15945.

  • Park JR. . 1995 Curr. Opin. Hematol. 3: 191–196.

  • Pircher TJ, Flores-Morales A, Mui AL, Saltiel AR, Norstedt G, Gustafsson JA and Haldosen L-A. . 1997 Mol. Cell. Endocrinol. 133: 169–176.

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

  • Rui H, Xu J, Mehta S, Fang H, Williams J, Dong F and Grimley PM. . 1998 J. Biol. Chem. 273: 28–32.

  • Schaefer TS, Sanders LK, Park OK and Nathans D. . 1997 Mol. Cell. Biol. 17: 5307–5316.

  • Schindler C. . 1998 Trends Cell Biol. 8: 97–98.

  • Schindler C, Fu XY, Improta T, Aebersold R and Darnell Jr JE. . 1992 Proc. Natl. Acad. Sci. USA 89: 7836–7839.

  • Schindler U, Wu P, Rothe M, Brasseur M and McKnight SL. . 1995 Immunity 2: 689–697.

  • Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D and Darnell Jr JE. . 1994 Cell 76: 821–828.

  • Shuai K, Ziemiecki A, Wilks AF, Harpur AG, Sadowski HB, Gilman MZ and Darnell JE. . 1993 Nature 366: 580–583.

  • Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell Jr JE and Yancopoulos GD. . 1995 Science 267: 1349–1353.

  • Teglund S, McKay C, Schuetsz E, van Deusen JM, Skavopodis D, Wang D, Brown M, Bodner S, Grosveld G and Ihle JN. . 1998 Cell 93: 841–850.

  • Thomas J, Leverrier Y and Marvel J. . 1998 Oncogene 16: 1399–1408.

  • Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ and Davey HW. . 1997 Proc. Natl. Acad. Sci. USA 94: 7239–7244.

  • Verdier F, Rabianet R, Gouilleux F, Beisenheuz-Huss C, Varlet P, Muller O, Mayeux P, Lacambe C, Gesselhecht S and Chetien S. . 1998 Mol. Cell. Biol. 18: 5852–5860.

  • Wakao H, Gouilleux F and Groner B. . 1994 EMBO J. 14: 854–855.

  • Wakao H, Harada N, Kitamura T, Mui AL and Miyajima A. . 1994 EMBO J. 14: 2527–2535.

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

  • Wen Z, Zhong Z and Darnell J. . 1995 Cell 82: 241–250.

  • Wood TJ, Sliva D, Lobie PE, Pircher TJ, Gouilleux F, Wakao H, Gustafsson JA, Groner B, Norstedt G and Haldosen LA. . 1995 J. Biol. Chem. 270: 9448–9453.

  • Yoshimura A, Ichihara M, Kinjyo I, Moriyama M, Copeland NG, Gilbert DJ, Jenkins NA, Hara T and Miyhajima A. . 1996 EMBO J. 15: 1055–1063.

  • Zamorano J, Wang HY, Wang R, Shi Y, Longmore GD and Keegan AD. . 1998 J. Immunol. 160: 3502–3512.

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Acknowledgements

The authors would like to thank E Gomas and F Letourneur for their help in DNA sequencing, Drs B Sola and S Chretien for providing the Bcl-x and the CIS cDNAs and Dr I Dusanter for critical reading of the manuscript. This work was supported by ARC (Association de Recherche contre le Cancer) and INSERM (Institut National de la Recherche Medicale). S Dumon, F Debierre-Grockiego and C Boucheron are supported by the Ministere de l'Education de la Recherche et de la Technologie (M.E.R.T.).

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Dumon, S., Santos, S., Debierre-Grockiego, F. et al. IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line. Oncogene 18, 4191–4199 (1999). https://doi.org/10.1038/sj.onc.1202796

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