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 Shinjyo, T.
Right arrow Articles by Inaba, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shinjyo, T.
Right arrow Articles by Inaba, T.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, February 2001, p. 854-864, Vol. 21, No. 3
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.3.854-864.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Downregulation of Bim, a Proapoptotic Relative of Bcl-2, Is a Pivotal Step in Cytokine-Initiated Survival Signaling in Murine Hematopoietic Progenitors

Tetsuharu Shinjyo,1 Ryoko Kuribara,1,2 Takeshi Inukai,3 Hajime Hosoi,4 Taisei Kinoshita,5 Atsushi Miyajima,5 Peter J. Houghton,6 A. Thomas Look,7 Keiya Ozawa,1,2 and Toshiya Inaba1,8,*

Departments of Molecular Biology1 and Hematology,2 Jichi Medical School, Tochigi 329-0498, Department of Pediatrics, Yamanashi Medical University, Yamanashi 409-3898,3 Department of Pediatrics, Kyoto Prefectural Medical School, Kyoto 606,4 Institute of Molecular and Cellular Bioscience, University of Tokyo, Tokyo 174,5 and Department of Molecular Oncology, Research Institute for Radation Biology and Medicine, Hiroshima University, Hiroshima 734-8553,8 Japan; Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis Tennessee 381056; and Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 021157

Received 17 July 2000/Returned for modification 20 September 2000/Accepted 2 November 2000

Two distinct signaling pathways regulate the survival of interleukin-3 (IL-3)-dependent hematopoietic progenitors. One originates from the membrane-proximal portion of the cytoplasmic domain of the IL-3 receptor (beta c chain), which is shared by IL-3 and granulocyte-macrophage colony-stimulating factor and is involved in the regulation of Bcl-xL through activation of STAT5. The other pathway emanates from the distal region of the beta c chain and overlaps with downstream signals from constitutively active Ras proteins. Although the latter pathway is indispensable for cell survival, its downstream targets remain largely undefined. Here we show that the expression of Bim, a member of the BH3-only subfamily of cell death activators, is downregulated by IL-3 signaling through either of two major Ras pathways: Raf/mitogen-activated protein kinase and the phosphatidylinositol 3-kinase/mammalian target of rapamycin. Akt/phosphokinase B does not appear to play a significant role in this regulatory cascade. Bim downregulation has important implications for cell survival, since enforced expression of this death activator at levels equivalent to those induced by cytokine withdrawal led to apoptosis even in the presence of IL-3. We conclude that Bim is a pivotal molecule in cytokine regulation of hematopoietic cell survival.

* Corresponding author. Mailing address: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Phone: 81-82-257-5834. Fax: 81-82-256-7103.

Molecular and Cellular Biology, February 2001, p. 854-864, Vol. 21, No. 3
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.3.854-864.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Sharma, S., Lichtenstein, A. (2008). Dexamethasone-induced apoptotic mechanisms in myeloma cells investigated by analysis of mutant glucocorticoid receptors. Blood 112: 1338-1345 [Abstract] [Full Text]  
  • Zhang, L., Zambon, A. C., Vranizan, K., Pothula, K., Conklin, B. R., Insel, P. A. (2008). Gene Expression Signatures of cAMP/Protein Kinase A (PKA)-promoted, Mitochondrial-dependent Apoptosis: COMPARATIVE ANALYSIS OF WILD-TYPE AND cAMP-DEATHLESS S49 LYMPHOMA CELLS. J. Biol. Chem. 283: 4304-4313 [Abstract] [Full Text]  
  • Woodland, R. T., Fox, C. J., Schmidt, M. R., Hammerman, P. S., Opferman, J. T., Korsmeyer, S. J., Hilbert, D. M., Thompson, C. B. (2008). Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival. Blood 111: 750-760 [Abstract] [Full Text]  
  • Deng, J., Shimamura, T., Perera, S., Carlson, N. E., Cai, D., Shapiro, G. I., Wong, K.-K., Letai, A. (2007). Proapoptotic BH3-Only BCL-2 Family Protein BIM Connects Death Signaling from Epidermal Growth Factor Receptor Inhibition to the Mitochondrion. Cancer Res. 67: 11867-11875 [Abstract] [Full Text]  
  • Pei, X.-Y., Dai, Y., Tenorio, S., Lu, J., Harada, H., Dent, P., Grant, S. (2007). MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism. Blood 110: 2092-2101 [Abstract] [Full Text]  
  • Hacker, G., Suttner, K., Harada, H., Kirschnek, S. (2006). TLR-dependent Bim phosphorylation in macrophages is mediated by ERK and is connected to proteasomal degradation of the protein. Int Immunol 18: 1749-1757 [Abstract] [Full Text]  
  • McCarty, M. F., Block, K. I. (2006). Preadministration of High-Dose Salicylates, Suppressors of NF-{kappa}B Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy. Integr Cancer Ther 5: 252-268 [Abstract]  
  • Yano, T., Ito, K., Fukamachi, H., Chi, X.-Z., Wee, H.-J., Inoue, K.-i., Ida, H., Bouillet, P., Strasser, A., Bae, S.-C., Ito, Y. (2006). The RUNX3 Tumor Suppressor Upregulates Bim in Gastric Epithelial Cells Undergoing Transforming Growth Factor {beta}-Induced Apoptosis. Mol. Cell. Biol. 26: 4474-4488 [Abstract] [Full Text]  
  • Meller, R., Cameron, J. A., Torrey, D. J., Clayton, C. E., Ordonez, A. N., Henshall, D. C., Minami, M., Schindler, C. K., Saugstad, J. A., Simon, R. P. (2006). Rapid Degradation of Bim by the Ubiquitin-Proteasome Pathway Mediates Short-term Ischemic Tolerance in Cultured Neurons. J. Biol. Chem. 281: 7429-7436 [Abstract] [Full Text]  
  • Haneline, L. S., White, H., Yang, F.-C., Chen, S., Orschell, C., Kapur, R., Ingram, D. A. (2006). Genetic reduction of class IA PI-3 kinase activity alters fetal hematopoiesis and competitive repopulating ability of hematopoietic stem cells in vivo. Blood 107: 1375-1382 [Abstract] [Full Text]  
  • Qi, X.-J., Wildey, G. M., Howe, P. H. (2006). Evidence That Ser87 of BimEL Is Phosphorylated by Akt and Regulates BimEL Apoptotic Function. J. Biol. Chem. 281: 813-823 [Abstract] [Full Text]  
  • Zhao, Y., Tan, J., Zhuang, L., Jiang, X., Liu, E. T., Yu, Q. (2005). Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim. Proc. Natl. Acad. Sci. USA 102: 16090-16095 [Abstract] [Full Text]  
  • Aichberger, K. J., Mayerhofer, M., Krauth, M.-T., Vales, A., Kondo, R., Derdak, S., Pickl, W. F., Selzer, E., Deininger, M., Druker, B. J., Sillaber, C., Esterbauer, H., Valent, P. (2005). Low-Level Expression of Proapoptotic Bcl-2-Interacting Mediator in Leukemic Cells in Patients with Chronic Myeloid Leukemia: Role of BCR/ABL, Characterization of Underlying Signaling Pathways, and Reexpression by Novel Pharmacologic Compounds. Cancer Res. 65: 9436-9444 [Abstract] [Full Text]  
  • Austin, M., Cook, S. J. (2005). Increased Expression of Mcl-1 Is Required for Protection against Serum Starvation in Phosphatase and Tensin Homologue on Chromosome 10 Null Mouse Embryonic Fibroblasts, but Repression of Bim Is Favored in Human Glioblastomas. J. Biol. Chem. 280: 33280-33288 [Abstract] [Full Text]  
  • Clybouw, C., Mchichi, B., Mouhamad, S., Auffredou, M. T., Bourgeade, M. F., Sharma, S., Leca, G., Vazquez, A. (2005). EBV Infection of Human B Lymphocytes Leads to Down-Regulation of Bim Expression: Relationship to Resistance to Apoptosis. J. Immunol. 175: 2968-2973 [Abstract] [Full Text]  
  • Moller, C., Alfredsson, J., Engstrom, M., Wootz, H., Xiang, Z., Lennartsson, J., Jonsson, J.-I., Nilsson, G. (2005). Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim. Blood 106: 1330-1336 [Abstract] [Full Text]  
  • Nyunoya, T., Monick, M. M., Powers, L. S., Yarovinsky, T. O., Hunninghake, G. W. (2005). Macrophages Survive Hyperoxia via Prolonged ERK Activation Due to Phosphatase Down-regulation. J. Biol. Chem. 280: 26295-26302 [Abstract] [Full Text]  
  • Reginato, M. J., Mills, K. R., Becker, E. B. E., Lynch, D. K., Bonni, A., Muthuswamy, S. K., Brugge, J. S. (2005). Bim Regulation of Lumen Formation in Cultured Mammary Epithelial Acini Is Targeted by Oncogenes. Mol. Cell. Biol. 25: 4591-4601 [Abstract] [Full Text]  
  • Luciano, F., Zhai, D., Zhu, X., Bailly-Maitre, B., Ricci, J.-E., Satterthwait, A. C., Reed, J. C. (2005). Cytoprotective Peptide Humanin Binds and Inhibits Proapoptotic Bcl-2/Bax Family Protein BimEL. J. Biol. Chem. 280: 15825-15835 [Abstract] [Full Text]  
  • Abrams, M. T., Robertson, N. M., Yoon, K., Wickstrom, E. (2004). Inhibition of Glucocorticoid-induced Apoptosis by Targeting the Major Splice Variants of BIM mRNA with Small Interfering RNA and Short Hairpin RNA. J. Biol. Chem. 279: 55809-55817 [Abstract] [Full Text]  
  • Harada, H., Quearry, B., Ruiz-Vela, A., Korsmeyer, S. J. (2004). Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity. Proc. Natl. Acad. Sci. USA 101: 15313-15317 [Abstract] [Full Text]  
  • Becker, E. B. E., Howell, J., Kodama, Y., Barker, P. A., Bonni, A. (2004). Characterization of the c-Jun N-Terminal Kinase-BimEL Signaling Pathway in Neuronal Apoptosis. J. Neurosci. 24: 8762-8770 [Abstract] [Full Text]  
  • Fukazawa, H., Noguchi, K., Masumi, A., Murakami, Y., Uehara, Y. (2004). BimEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors. Molecular Cancer Therapeutics 3: 1281-1288 [Abstract] [Full Text]  
  • Andoniou, C. E., Andrews, D. M., Manzur, M., Ricciardi-Castagnoli, P., Degli-Esposti, M. A. (2004). A novel checkpoint in the Bcl-2-regulated apoptotic pathway revealed by murine cytomegalovirus infection of dendritic cells. JCB 166: 827-837 [Abstract] [Full Text]  
  • Valentijn, A. J., Gilmore, A. P. (2004). Translocation of Full-length Bid to Mitochondria during Anoikis. J. Biol. Chem. 279: 32848-32857 [Abstract] [Full Text]  
  • Kuribara, R., Honda, H., Matsui, H., Shinjyo, T., Inukai, T., Sugita, K., Nakazawa, S., Hirai, H., Ozawa, K., Inaba, T. (2004). Roles of Bim in Apoptosis of Normal and Bcr-Abl-Expressing Hematopoietic Progenitors. Mol. Cell. Biol. 24: 6172-6183 [Abstract] [Full Text]  
  • Zhang, L., Insel, P. A. (2004). The Pro-apoptotic Protein Bim Is a Convergence Point for cAMP/Protein Kinase A- and Glucocorticoid-promoted Apoptosis of Lymphoid Cells. J. Biol. Chem. 279: 20858-20865 [Abstract] [Full Text]  
  • del Carmen Rodriguez, M., Bernad, A., Aracil, M. (2004). Interleukin-6 deficiency affects bone marrow stromal precursors, resulting in defective hematopoietic support. Blood 103: 3349-3354 [Abstract] [Full Text]  
  • Matsunaga, T., Inaba, T., Matsui, H., Okuya, M., Miyajima, A., Inukai, T., Funabiki, T., Endo, M., Look, A. T., Kurosawa, H. (2004). Regulation of annexin II by cytokine-initiated signaling pathways and E2A-HLF oncoprotein. Blood 103: 3185-3191 [Abstract] [Full Text]  
  • Ley, R., Ewings, K. E., Hadfield, K., Howes, E., Balmanno, K., Cook, S. J. (2004). Extracellular Signal-regulated Kinases 1/2 Are Serum-stimulated "BimEL Kinases" That Bind to the BH3-only Protein BimEL Causing Its Phosphorylation and Turnover. J. Biol. Chem. 279: 8837-8847 [Abstract] [Full Text]  
  • Sandalova, E., Wei, C.-H., Masucci, M. G., Levitsky, V. (2004). Regulation of expression of Bcl-2 protein family member Bim by T cell receptor triggering. Proc. Natl. Acad. Sci. USA 101: 3011-3016 [Abstract] [Full Text]  
  • Mouhamad, S., Besnault, L., Auffredou, M. T., Leprince, C., Bourgeade, M. F., Leca, G., Vazquez, A. (2004). B Cell Receptor-Mediated Apoptosis of Human Lymphocytes Is Associated with a New Regulatory Pathway of Bim Isoform Expression. J. Immunol. 172: 2084-2091 [Abstract] [Full Text]  
  • Pellegrini, M., Belz, G., Bouillet, P., Strasser, A. (2003). Shutdown of an acute T cell immune response to viral infection is mediated by the proapoptotic Bcl-2 homology 3-only protein Bim. Proc. Natl. Acad. Sci. USA 100: 14175-14180 [Abstract] [Full Text]  
  • Minami, Y., Yamamoto, K., Kiyoi, H., Ueda, R., Saito, H., Naoe, T. (2003). Different antiapoptotic pathways between wild-type and mutated FLT3: insights into therapeutic targets in leukemia. Blood 102: 2969-2975 [Abstract] [Full Text]  
  • White, E. (2003). The pims and outs of survival signaling: role for the Pim-2 protein kinase in the suppression of apoptosis by cytokines. Genes Dev. 17: 1813-1816 [Full Text]  
  • Wang, Z., Malone, M. H., He, H., McColl, K. S., Distelhorst, C. W. (2003). Microarray Analysis Uncovers the Induction of the Proapoptotic BH3-only Protein Bim in Multiple Models of Glucocorticoid-induced Apoptosis. J. Biol. Chem. 278: 23861-23867 [Abstract] [Full Text]  
  • Ley, R., Balmanno, K., Hadfield, K., Weston, C., Cook, S. J. (2003). Activation of the ERK1/2 Signaling Pathway Promotes Phosphorylation and Proteasome-dependent Degradation of the BH3-only Protein, Bim. J. Biol. Chem. 278: 18811-18816 [Abstract] [Full Text]  
  • Wildey, G. M., Patil, S., Howe, P. H. (2003). Smad3 Potentiates Transforming Growth Factor beta (TGFbeta )-induced Apoptosis and Expression of the BH3-only Protein Bim in WEHI 231 B Lymphocytes. J. Biol. Chem. 278: 18069-18077 [Abstract] [Full Text]  
  • Tepera, S. B., McCrea, P. D., Rosen, J. M. (2003). A {beta}-catenin survival signal is required for normal lobular development in the mammary gland. J. Cell Sci. 116: 1137-1149 [Abstract] [Full Text]  
  • Lei, K., Davis, R. J. (2003). JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc. Natl. Acad. Sci. USA 100: 2432-2437 [Abstract] [Full Text]  
  • Komatsu, N., Watanabe, T., Uchida, M., Mori, M., Kirito, K., Kikuchi, S., Liu, Q., Tauchi, T., Miyazawa, K., Endo, H., Nagai, T., Ozawa, K. (2003). A Member of Forkhead Transcription Factor FKHRL1 Is a Downstream Effector of STI571-induced Cell Cycle Arrest in BCR-ABL-expressing Cells. J. Biol. Chem. 278: 6411-6419 [Abstract] [Full Text]  
  • Biswas, S. C., Greene, L. A. (2002). Nerve Growth Factor (NGF) Down-regulates the Bcl-2 Homology 3 (BH3) Domain-only Protein Bim and Suppresses Its Proapoptotic Activity by Phosphorylation. J. Biol. Chem. 277: 49511-49516 [Abstract] [Full Text]  
  • Yamaguchi, H., Wang, H.-G. (2002). Bcl-XL Protects BimEL-induced Bax Conformational Change and Cytochrome c Release Independent of Interacting with Bax or BimEL. J. Biol. Chem. 277: 41604-41612 [Abstract] [Full Text]  
  • Stahl, M., Dijkers, P. F., Kops, G. J. P. L., Lens, S. M. A., Coffer, P. J., Burgering, B. M. T., Medema, R. H. (2002). The Forkhead Transcription Factor FoxO Regulates Transcription of p27Kip1 and Bim in Response to IL-2. J. Immunol. 168: 5024-5031 [Abstract] [Full Text]  
  • Li, L., Liu, D., Hutt-Fletcher, L., Morgan, A., Masucci, M. G., Levitsky, V. (2002). Epstein-Barr virus inhibits the development of dendritic cells by promoting apoptosis of their monocyte precursors in the presence of granulocyte macrophage-colony-stimulating factor and interleukin-4. Blood 99: 3725-3734 [Abstract] [Full Text]  
  • Kirito, K., Watanabe, T., Sawada, K.-i., Endo, H., Ozawa, K., Komatsu, N. (2002). Thrombopoietin Regulates Bcl-xL Gene Expression through Stat5 and Phosphatidylinositol 3-Kinase Activation Pathways. J. Biol. Chem. 277: 8329-8337 [Abstract] [Full Text]  
  • Claessens, Y.-E., Bouscary, D., Dupont, J.-M., Picard, F., Melle, J., Gisselbrecht, S., Lacombe, C., Dreyfus, F., Mayeux, P., Fontenay-Roupie, M. (2002). In vitro proliferation and differentiation of erythroid progenitors from patients with myelodysplastic syndromes: evidence for Fas-dependent apoptosis. Blood 99: 1594-1601 [Abstract] [Full Text]  
  • Dijkers, P. F., Birkenkamp, K. U., Lam, E. W.-F., Thomas, N. S. B., Lammers, J.-W. J., Koenderman, L., Coffer, P. J. (2002). FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity. JCB 156: 531-542 [Abstract] [Full Text]  
  • Wang, X. (2001). The expanding role of mitochondria in apoptosis. Genes Dev. 15: 2922-2933 [Full Text]  
  • Castedo, M., Ferri, K. F., Blanco, J., Roumier, T., Larochette, N., Barretina, J., Amendola, A., Nardacci, R., Metivier, D., Este, J. A., Piacentini, M., Kroemer, G. (2001). Human Immunodeficiency Virus 1 Envelope Glycoprotein Complex-Induced Apoptosis Involves Mammalian Target of Rapamycin/Fkbp12-Rapamycin-Associated Protein-Mediated P53 Phosphorylation. JEM 194: 1097-1110 [Abstract] [Full Text]  
  • Han, J.-w., Flemington, C., Houghton, A. B., Gu, Z., Zambetti, G. P., Lutz, R. J., Zhu, L., Chittenden, T. (2001). Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc. Natl. Acad. Sci. USA 98: 11318-11323 [Abstract] [Full Text]  
  • Dijkers, P. F., Birkenkamp, K. U., Lam, E. W.-F., Thomas, N. S. B., Lammers, J.-W. J., Koenderman, L., Coffer, P. J. (2002). FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity. JCB 156: 531-542 [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»