This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Neshat, M. S.
Right arrow Articles by Sawyers, C. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Neshat, M. S.
Right arrow Articles by Sawyers, C. L.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, February 2000, p. 1179-1186, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Survival Function of the Bcr-Abl Oncogene Is Mediated by Bad-Dependent and -Independent Pathways: Roles for Phosphatidylinositol 3-Kinase and Raf

Mehran S. Neshat,1,2 Arthur B. Raitano,1 Hong-Gang Wang,3 John C. Reed,3 and Charles L. Sawyers1,2,*

Departments of Medicine1 and Molecular Biology Institute,2 University of California, Los Angeles, and Program on Apoptosis and Cell Death Research, Burnham Institute, La Jolla,3 California

Received 25 October 1999/Accepted 10 November 1999

The Bcr-Abl tyrosine kinase constitutively activates cytokine signal transduction pathways that stimulate growth and prevent apoptosis in hematopoietic cells. The antiapoptotic action of interleukin-3 (IL-3) has been linked to a signaling pathway which inactivates the proapoptotic protein Bad by phosphorylation through kinases such as Akt and Raf. Here we report also that expression of Bcr-Abl leads to phosphorylation of Bad in hematopoietic cells. Bad phosphorylation induced by Bcr-Abl is kinase dependent, requires phosphatidylinositol 3-kinase (PI3-kinase), and mitochondrial targeting of Raf, and occurs independently of Erk. The ability of Bcr-Abl to confer cytokine-independent survival to hematopoietic cells was compromised by inhibitors of PI3-kinase, as well as by a dominant negative form of Raf targeted to the mitochondria. Furthermore, when the capacity of Bcr-Abl to phosphorylate Bad was completely blocked by dominant negative Raf, a subpopulation of cells remained viable, providing evidence for Bad-independent survival pathways. This alternative survival pathway remained PI3-kinase dependent. Finally, Bcr-Abl, but not IL-3, inhibited the proapoptotic activity of overexpressed Bad. We conclude that the antiapoptotic function of Bcr-Abl is mediated through pathways involving PI3-kinase and Raf and that survival can occur in the absence of Bad phosphorylation.

* Corresponding author. Mailing address: 11-934 Factor Building, UCLA/Hematology-Oncology, 10833 Le Conte Ave., Los Angeles, CA 90095-1678. Phone: (310) 206-5585. Fax: (310) 206-8502. E-mail: csawyers{at}mednet.ucla.edu.

Molecular and Cellular Biology, February 2000, p. 1179-1186, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Jagani, Z., Song, K., Kutok, J. L., Dewar, M. R., Melet, A., Santos, T., Grassian, A., Ghaffari, S., Wu, C., Ren, R., Rodin, H. Y., Miller, K., Khosravi-Far, R. (2009). Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL-Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors. Cancer Res. 69: 6546-6555 [Abstract] [Full Text]  
  • Kurokawa, M., Zhao, C., Reya, T., Kornbluth, S. (2008). Inhibition of Apoptosome Formation by Suppression of Hsp90{beta} Phosphorylation in Tyrosine Kinase-Induced Leukemias. Mol. Cell. Biol. 28: 5494-5506 [Abstract] [Full Text]  
  • Vance, J. E. (2008). Thematic Review Series: Glycerolipids. Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids. J. Lipid Res. 49: 1377-1387 [Abstract] [Full Text]  
  • Dasmahapatra, G., Yerram, N., Dai, Y., Dent, P., Grant, S. (2007). Synergistic Interactions between Vorinostat and Sorafenib in Chronic Myelogenous Leukemia Cells Involve Mcl-1 and p21CIP1 Down-Regulation. Clin. Cancer Res. 13: 4280-4290 [Abstract] [Full Text]  
  • Yoshida, C., Yoshida, F., Sears, D. E., Hart, S. M., Ikebe, D., Muto, A., Basu, S., Igarashi, K., Melo, J. V. (2007). Bcr-Abl signaling through the PI-3/S6 kinase pathway inhibits nuclear translocation of the transcription factor Bach2, which represses the antiapoptotic factor heme oxygenase-1. Blood 109: 1211-1219 [Abstract] [Full Text]  
  • Li, M., Welti, R., Wang, X. (2006). Quantitative Profiling of Arabidopsis Polar Glycerolipids in Response to Phosphorus Starvation. Roles of Phospholipases D{zeta}1 and D{zeta}2 in Phosphatidylcholine Hydrolysis and Digalactosyldiacylglycerol Accumulation in Phosphorus-Starved Plants. Plant Physiol. 142: 750-761 [Abstract] [Full Text]  
  • Ren, S.-y., Bolton, E., Mohi, M. G., Morrione, A., Neel, B. G., Skorski, T. (2005). Phosphatidylinositol 3-Kinase p85{alpha} Subunit-Dependent Interaction with BCR/ABL-Related Fusion Tyrosine Kinases: Molecular Mechanisms and Biological Consequences. Mol. Cell. Biol. 25: 8001-8008 [Abstract] [Full Text]  
  • Hickey, F. B., England, K., Cotter, T. G. (2005). Bcr-Abl regulates osteopontin transcription via Ras, PI-3K, aPKC, Raf-1, and MEK. J. Leukoc. Biol. 78: 289-300 [Abstract] [Full Text]  
  • Jin, S., Zhuo, Y., Guo, W., Field, J. (2005). p21-activated Kinase 1 (Pak1)-dependent Phosphorylation of Raf-1 Regulates Its Mitochondrial Localization, Phosphorylation of BAD, and Bcl-2 Association. J. Biol. Chem. 280: 24698-24705 [Abstract] [Full Text]  
  • Tseng, P.-H., Lin, H.-P., Zhu, J., Chen, K.-F., Hade, E. M., Young, D. C., Byrd, J. C., Grever, M., Johnson, K., Druker, B. J., Chen, C.-S. (2005). Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance. Blood 105: 4021-4027 [Abstract] [Full Text]  
  • Kharas, M. G., Fruman, D. A. (2005). ABL Oncogenes and Phosphoinositide 3-Kinase: Mechanism of Activation and Downstream Effectors. Cancer Res. 65: 2047-2053 [Abstract] [Full Text]  
  • Baughn, L. B., Rosenberg, N. (2005). Disruption of the Shc/Grb2 Complex during Abelson Virus Transformation Affects Proliferation, but Not Apoptosis. J. Virol. 79: 2325-2334 [Abstract] [Full Text]  
  • George, P., Bali, P., Annavarapu, S., Scuto, A., Fiskus, W., Guo, F., Sigua, C., Sondarva, G., Moscinski, L., Atadja, P., Bhalla, K. (2005). Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood 105: 1768-1776 [Abstract] [Full Text]  
  • Guo, F., Sigua, C., Bali, P., George, P., Fiskus, W., Scuto, A., Annavarapu, S., Mouttaki, A., Sondarva, G., Wei, S., Wu, J., Djeu, J., Bhalla, K. (2005). Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. Blood 105: 1246-1255 [Abstract] [Full Text]  
  • Deming, P. B., Schafer, Z. T., Tashker, J. S., Potts, M. B., Deshmukh, M., Kornbluth, S. (2004). Bcr-Abl-Mediated Protection from Apoptosis Downstream of Mitochondrial Cytochrome c Release. Mol. Cell. Biol. 24: 10289-10299 [Abstract] [Full Text]  
  • O'Hare, T., Pollock, R., Stoffregen, E. P., Keats, J. A., Abdullah, O. M., Moseson, E. M., Rivera, V. M., Tang, H., Metcalf, C. A. III, Bohacek, R. S., Wang, Y., Sundaramoorthi, R., Shakespeare, W. C., Dalgarno, D., Clackson, T., Sawyer, T. K., Deininger, M. W., Druker, B. J. (2004). Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML. Blood 104: 2532-2539 [Abstract] [Full Text]  
  • Dai, Y., Rahmani, M., Corey, S. J., Dent, P., Grant, S. (2004). A Bcr/Abl-independent, Lyn-dependent Form of Imatinib Mesylate (STI-571) Resistance Is Associated with Altered Expression of Bcl-2. J. Biol. Chem. 279: 34227-34239 [Abstract] [Full Text]  
  • Dai, Y., Rahmani, M., Pei, X.-Y., Dent, P., Grant, S. (2004). Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Blood 104: 509-518 [Abstract] [Full Text]  
  • Nimmanapalli, R., Bali, P., O'Bryan, E., Fuino, L., Guo, F., Wu, J., Houghton, P., Bhalla, K. (2003). Arsenic Trioxide Inhibits Translation of mRNA of bcr-abl, Resulting in Attenuation of Bcr-Abl Levels and Apoptosis of Human Leukemia Cells. Cancer Res. 63: 7950-7958 [Abstract] [Full Text]  
  • Yan, B., Zemskova, M., Holder, S., Chin, V., Kraft, A., Koskinen, P. J., Lilly, M. (2003). The PIM-2 Kinase Phosphorylates BAD on Serine 112 and Reverses BAD-induced Cell Death. J. Biol. Chem. 278: 45358-45367 [Abstract] [Full Text]  
  • Clark, S. S., Zhong, L., Filiault, D., Perman, S., Ren, Z., Gould, M., Yang, X. (2003). Anti-Leukemia Effect of Perillyl Alcohol in Bcr/Abl-Transformed Cells Indirectly Inhibits Signaling through Mek in a Ras- and Raf-Independent Fashion. Clin. Cancer Res. 9: 4494-4504 [Abstract] [Full Text]  
  • Laurent, E., Mitchell, D. L., Estrov, Z., Lowery, M., Tucker, S. L., Talpaz, M., Kurzrock, R. (2003). Impact of p210Bcr-Abl on Ultraviolet C Wavelength-induced DNA Damage and Repair. Clin. Cancer Res. 9: 3722-3730 [Abstract] [Full Text]  
  • Ghaffari, S., Jagani, Z., Kitidis, C., Lodish, H. F., Khosravi-Far, R. (2003). Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc. Natl. Acad. Sci. USA 100: 6523-6528 [Abstract] [Full Text]  
  • Wong, S., McLaughlin, J., Cheng, D., Witte, O. N. (2003). Cell context-specific effects of the BCR-ABL oncogene monitored in hematopoietic progenitors. Blood 101: 4088-4097 [Abstract] [Full Text]  
  • Yu, C., Rahmani, M., Almenara, J., Subler, M., Krystal, G., Conrad, D., Varticovski, L., Dent, P., Grant, S. (2003). Histone Deacetylase Inhibitors Promote STI571-mediated Apoptosis in STI571-sensitive and -resistant Bcr/Abl+ Human Myeloid Leukemia Cells. Cancer Res. 63: 2118-2126 [Abstract] [Full Text]  
  • Nimmanapalli, R., Fuino, L., Stobaugh, C., Richon, V., Bhalla, K. (2003). Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood 101: 3236-3239 [Abstract] [Full Text]  
  • Golas, J. M., Arndt, K., Etienne, C., Lucas, J., Nardin, D., Gibbons, J., Frost, P., Ye, F., Boschelli, D. H., Boschelli, F. (2003). SKI-606, a 4-Anilino-3-quinolinecarbonitrile Dual Inhibitor of Src and Abl Kinases, Is a Potent Antiproliferative Agent against Chronic Myelogenous Leukemia Cells in Culture and Causes Regression of K562 Xenografts in Nude Mice. Cancer Res. 63: 375-381 [Abstract] [Full Text]  
  • Donato, N. J., Wu, J. Y., Stapley, J., Gallick, G., Lin, H., Arlinghaus, R., Talpaz, M. (2003). BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 101: 690-698 [Abstract] [Full Text]  
  • Smith, D. L., Evans, C. A., Pierce, A., Gaskell, S. J., Whetton, A. D. (2002). Changes in the Proteome Associated with the Action of Bcr-Abl Tyrosine Kinase Are Not Related to Transcriptional Regulation. Mol. Cell. Proteomics 1: 876-884 [Abstract] [Full Text]  
  • Nimmanapalli, R., O'Bryan, E., Huang, M., Bali, P., Burnette, P. K., Loughran, T., Tepperberg, J., Jove, R., Bhalla, K. (2002). Molecular Characterization and Sensitivity of STI-571 (Imatinib Mesylate, Gleevec)-resistant, Bcr-Abl-positive, Human Acute Leukemia Cells to SRC Kinase Inhibitor PD180970 and 17-Allylamino-17-demethoxygeldanamycin. Cancer Res. 62: 5761-5769 [Abstract] [Full Text]  
  • Dos Santos, P., Kowaltowski, A. J., Laclau, M. N., Seetharaman, S., Paucek, P., Boudina, S., Thambo, J.-B., Tariosse, L., Garlid, K. D. (2002). Mechanisms by which opening the mitochondrial ATP- sensitive K+ channel protects the ischemic heart. Am. J. Physiol. Heart Circ. Physiol. 283: H284-H295 [Abstract] [Full Text]  
  • Hindley, A., Kolch, W. (2002). Extracellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK)-independent functions of Raf kinases. J. Cell Sci. 115: 1575-1581 [Abstract] [Full Text]  
  • Sonoyama, J., Matsumura, I., Ezoe, S., Satoh, Y., Zhang, X., Kataoka, Y., Takai, E., Mizuki, M., Machii, T., Wakao, H., Kanakura, Y. (2002). Functional Cooperation among Ras, STAT5, and Phosphatidylinositol 3-Kinase Is Required for Full Oncogenic Activities of BCR/ABL in K562 Cells. J. Biol. Chem. 277: 8076-8082 [Abstract] [Full Text]  
  • Dierov, J., Xu, Q., Dierova, R., Carroll, M. (2002). TEL/platelet-derived growth factor receptor beta activates phosphatidylinositol 3 (PI3) kinase and requires PI3 kinase to regulate the cell cycle. Blood 99: 1758-1765 [Abstract] [Full Text]  
  • Dorsey, J. F., Cunnick, J. M., Mane, S. M., Wu, J. (2002). Regulation of the Erk2-Elk1 signaling pathway and megakaryocytic differentiation of Bcr-Abl+ K562 leukemic cells by Gab2. Blood 99: 1388-1397 [Abstract] [Full Text]  
  • Schimmer, A. D., Hedley, D. W., Penn, L. Z., Minden, M. D. (2001). Receptor- and mitochondrial-mediated apoptosis in acute leukemia: a translational view. Blood 98: 3541-3553 [Full Text]  
  • Guasch, G., Ollendorff, V., Borg, J.-P., Birnbaum, D., Pebusque, M.-J. (2001). 8p12 Stem Cell Myeloproliferative Disorder: the FOP-Fibroblast Growth Factor Receptor 1 Fusion Protein of the t(6;8) Translocation Induces Cell Survival Mediated by Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt/mTOR Pathways. Mol. Cell. Biol. 21: 8129-8142 [Abstract] [Full Text]  
  • Gelfanov, V. M., Burgess, G. S., Litz-Jackson, S., King, A. J., Marshall, M. S., Nakshatri, H., Boswell, H. S. (2001). Transformation of interleukin-3-dependent cells without participation of Stat5/bcl-xL: cooperation of akt with raf/erk leads to p65 nuclear factor {kappa}B-mediated antiapoptosis involving c-IAP2. Blood 98: 2508-2517 [Abstract] [Full Text]  
  • Goetz, A. W., van der Kuip, H., Maya, R., Oren, M., Aulitzky, W. E. (2001). Requirement for Mdm2 in the Survival Effects of Bcr-Abl and Interleukin 3 in Hematopoietic Cells. Cancer Res. 61: 7635-7641 [Abstract] [Full Text]  
  • van der Kuip, H., Goetz, A. W., Miething, C., Duyster, J., Aulitzky, W. E. (2001). Adhesion to fibronectin selectively protects Bcr-Abl+ cells from DNA damage-induced apoptosis. Blood 98: 1532-1541 [Abstract] [Full Text]  
  • Donato, N. J., Wu, J. Y., Zhang, L., Kantarjian, H., Talpaz, M. (2001). Down-regulation of interleukin-3/granulocyte-macrophage colony-stimulating factor receptor {beta}-chain in BCR-ABL+ human leukemic cells: association with loss of cytokine-mediated Stat-5 activation and protection from apoptosis after BCR-ABL inhibition. Blood 97: 2846-2853 [Abstract] [Full Text]  
  • Tomasson, M. H., Williams, I. R., Li, S., Kutok, J., Cain, D., Gillessen, S., Dranoff, G., Van Etten, R. A., Gilliland, D. G. (2001). Induction of myeloproliferative disease in mice by tyrosine kinase fusion oncogenes does not require granulocyte-macrophage colony-stimulating factor or interleukin-3. Blood 97: 1435-1441 [Abstract] [Full Text]  
  • Deininger, M. W. N., Goldman, J. M., Melo, J. V. (2000). The molecular biology of chronic myeloid leukemia. Blood 96: 3343-3356 [Full Text]  
  • Jung, F., Haendeler, J., Goebel, C., Zeiher, A. M., Dimmeler, S. (2000). Growth factor-induced phosphoinositide 3-OH kinase/Akt phosphorylation in smooth muscle cells: induction of cell proliferation and inhibition of cell death. Cardiovasc Res 48: 148-157 [Abstract] [Full Text]  
  • Gesbert, F., Griffin, J. D. (2000). Bcr/Abl activates transcription of the Bcl-X gene through STAT5. Blood 96: 2269-2276 [Abstract] [Full Text]  
  • Kim, H.-Y., Akbar, M., Lau, A., Edsall, L. (2000). Inhibition of Neuronal Apoptosis by Docosahexaenoic Acid (22:6n-3). ROLE OF PHOSPHATIDYLSERINE IN ANTIAPOPTOTIC EFFECT. J. Biol. Chem. 275: 35215-35223 [Abstract] [Full Text]  
  • Gesbert, F., Sellers, W. R., Signoretti, S., Loda, M., Griffin, J. D. (2000). BCR/ABL Regulates Expression of the Cyclin-dependent Kinase Inhibitor p27Kip1 through the Phosphatidylinositol 3-Kinase/AKT Pathway. J. Biol. Chem. 275: 39223-39230 [Abstract] [Full Text]  
  • Parada, Y., Banerji, L., Glassford, J., Lea, N. C., Collado, M., Rivas, C., Lewis, J. L., Gordon, M. Y., Thomas, N. S. B., Lam, E. W.-F. (2001). BCR-ABL and Interleukin 3 Promote Haematopoietic Cell Proliferation and Survival through Modulation of Cyclin D2 and p27Kip1 Expression. J. Biol. Chem. 276: 23572-23580 [Abstract] [Full Text]  
  • Nguyen, M. H.-H., Ho, J. M.-Y., Beattie, B. K., Barber, D. L. (2001). TEL-JAK2 Mediates Constitutive Activation of the Phosphatidylinositol 3'-Kinase/Protein Kinase B Signaling Pathway. J. Biol. Chem. 276: 32704-32713 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»