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The Journal of Immunology, Vol 144, Issue 9 3602-3610, Copyright © 1990 by American Association of Immunologists


ARTICLES

Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines

G Nunez, L London, D Hockenbery, M Alexander, JP McKearn and SJ Korsmeyer
Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110.

The t(14;18) of human follicular B cell lymphoma translocates the Bcl-2 gene into the Ig H chain locus and markedly deregulates Bcl-2 expression. We sought to determine if Bcl-2 could be directly implicated in a growth-factor pathway. Consequently, we introduced a retrovirus containing the murine Bcl-2 gene (N2-M-Bcl-2) or the parental retrovirus (N2) into a series of factor-dependent hemopoietic cell lines. Overexpressed Bcl-2 resulted in no long term IL-2, IL-3, or IL-6 independent clones, indicating that Bcl-2 could not spare the need for a specific ligand-receptor interaction. However, Bcl-2 did extend the short term survival of IL-3-dependent cell lines after factor deprivation. Although viable, IL-3-deprived pro B lymphocytes (FL5.12) bearing N2-M-Bcl-2 were in Go, and deregulated Bcl-2 did not obviously influence cell-cycle progression. Bcl-2 predominant effects were to delay the onset of cell death and to modestly augment viable cell growth in the first 48 h after IL-3 deprivation. This death sparing was associated with increased levels of Bcl-2 RNA and protein in factor- deprived cells possessing N2-M-Bcl-2. This result was not restricted to prolymphocytes because an IL-3-dependent mast cell line (32D) as well as a promyeloid line (FDC-P1) demonstrated the same response to Bcl-2. Moreover, the effect was not limited to the IL-3/IL-3R signal transduction pathway in that promyeloid cells maintained in granulocyte- macrophage-CSF or IL-4 displayed a similar response. Yet, Bcl-2- enhanced cell survival was not universal as an IL-2-dependent T cell line, and an IL-6-dependent myeloma line demonstrated no consistent effect upon IL withdrawal. Thus, Bcl-2 appears to interfere with cell death but in a cell type and/or factor-restricted fashion.


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Blood, August 1, 1998; 92(3): 959 - 967.
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J. Zamorano and A. D. Keegan
Regulation of Apoptosis by Tyrosine-Containing Domains of IL-4R{alpha}: Y497 and Y713, But Not the STAT6-Docking Tyrosines, Signal Protection from Apoptosis
J. Immunol., July 15, 1998; 161(2): 859 - 867.
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M. Schirmer, A. N. Vallejo, C. M. Weyand, and J. J. Goronzy
Resistance to Apoptosis and Elevated Expression of Bcl-2 in Clonally Expanded CD4+CD28- T Cells from Rheumatoid Arthritis Patients
J. Immunol., July 15, 1998; 161(2): 1018 - 1025.
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J. P. Fabisiak, V. E. Kagan, Y. Y. Tyurina, V. A. Tyurin, and J. S. Lazo
Paraquat-induced phosphatidylserine oxidation and apoptosis are independent of activation of PLA2
Am J Physiol Lung Cell Mol Physiol, May 1, 1998; 274(5): L793 - L802.
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N. Inohara, D. Ekhterae, I. Garcia, R. Carrio, J. Merino, A. Merry, S. Chen, and G. Nunez
Mtd, a Novel Bcl-2 Family Member Activates Apoptosis in the Absence of Heterodimerization with Bcl-2 and Bcl-XL
J. Biol. Chem., April 10, 1998; 273(15): 8705 - 8710.
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R. Hegde, S. M. Srinivasula, M. Ahmad, T. Fernandes-Alnemri, and E. S. Alnemri
Blk, a BH3-containing Mouse Protein That Interacts with Bcl-2 and Bcl-xL, Is a Potent Death Agonist
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S. Moffatt, N. Yaegashi, K. Tada, N. Tanaka, and K. Sugamura
Human Parvovirus B19 Nonstructural (NS1) Protein Induces Apoptosis in Erythroid Lineage Cells
J. Virol., April 1, 1998; 72(4): 3018 - 3028.
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J. Zamorano, H. Y. Wang, R. Wang, Y. Shi, G. D. Longmore, and A. D. Keegan
Regulation of Cell Growth by IL-2: Role of STAT5 in Protection from Apoptosis But Not in Cell Cycle Progression
J. Immunol., April 1, 1998; 160(7): 3502 - 3512.
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BloodHome page
J. L. Gommerman and S. A. Berger
Protection From Apoptosis by Steel Factor But Not Interleukin-3 Is Reversed Through Blockade of Calcium Influx
Blood, March 15, 1998; 91(6): 1891 - 1900.
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BloodHome page
E. Gubina, M.S. Rinaudo, Z. Szallasi, P.M. Blumberg, and R.A. Mufson
Overexpression of Protein Kinase C Isoform [IMAGE] but not delta  in Human Interleukin-3-Dependent Cells Suppresses Apoptosis and Induces bcl-2 Expression
Blood, February 1, 1998; 91(3): 823 - 829.
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BloodHome page
N. Shirafuji, S. Takahashi, S. Matsuda, and S. Asano
Mitochondrial Antisense RNA for Cytochrome C Oxidase (MARCO) Can Induce Morphologic Changes and Cell Death in Human Hematopoietic Cell Lines
Blood, December 1, 1997; 90(11): 4567 - 4577.
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ScienceHome page
A. T. Look
Oncogenic Transcription Factors in the Human Acute Leukemias
Science, November 7, 1997; 278(5340): 1059 - 1064.
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BloodHome page
V. Lacronique, P. Varlet, P. Mayeux, A. Porteu, S. Gisselbrecht, A. Kahn, and C. Lacombe
Bcl-2 Targeted Overexpression Into the Erythroid Lineage of Transgenic Mice Delays But Does Not Prevent the Apoptosis of Erythropoietin-Deprived Erythroid Progenitors
Blood, October 15, 1997; 90(8): 3050 - 3056.
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Proc. Natl. Acad. Sci. USAHome page
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Interleukin 3-dependent survival by the Akt protein kinase
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Reproductive SciencesHome page
G. F. Erickson
Defining Apoptosis: Players and Systems
Reproductive Sciences, September 1, 1997; 4(5): 219 - 228.
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J. Clin. Endocrinol. Metab.Home page
X.-J. Tao, K. I. Tilly, D. V. Maravei, J. L. Shifren, S. Krajewski, J. C. Reed, J. L. Tilly, and K. B. Isaacson
Differential Expression of Members of the bcl-2 Gene Family in Proliferative and Secretory Human Endometrium: Glandular Epithelial Cell Apoptosis Is Associated with Increased Expression of bax
J. Clin. Endocrinol. Metab., August 1, 1997; 82(8): 2738 - 2746.
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BloodHome page
P. L. Simonian, D. A.M. Grillot, and G. Nunez
Bcl-2 and Bcl-XL Can Differentially Block Chemotherapy-Induced Cell Death
Blood, August 1, 1997; 90(3): 1208 - 1216.
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BloodHome page
P. A. Gregoli and M. C. Bondurant
The Roles of Bcl-XL and Apopain in the Control of Erythropoiesis by Erythropoietin
Blood, July 15, 1997; 90(2): 630 - 640.
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Mol. Endocrinol.Home page
C. V. Clevenger, K. Thickman, W. Ngo, W.-P. Chang, S. Takayama, and J. C. Reed
Role of Bag-1 in the Survival and Proliferation of the Cytokine-Dependent Lymphocyte Lines, Ba/F3 and Nb2
Mol. Endocrinol., May 1, 1997; 11(5): 608 - 618.
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BloodHome page
C. Sanz, A. Benito, M. Silva, B. Albella, C. Richard, J. C. Segovia, A. Insunza, J. A. Bueren, and J. L. Fernandez-Luna
The Expression of Bcl-x Is Downregulated During Differentiation of Human Hematopoietic Progenitor Cells Along the Granulocyte But Not the Monocyte/Macrophage Lineage
Blood, May 1, 1997; 89(9): 3199 - 3204.
[Abstract] [Full Text] [PDF]


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BloodHome page
L. M. Osorio, A. De Santiago, M. Aguilar-SantelisesHa, k. Mellstedt, and M. Jondal
CD6 Ligation Modulates the Bcl-2/Bax Ratio and Protects Chronic Lymphocytic Leukemia B Cells From Apoptosis Induced by Anti-IgM
Blood, April 15, 1997; 89(8): 2833 - 2841.
[Abstract] [Full Text] [PDF]


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BloodHome page
H. W. Findley, L. Gu, A. M. Yeager, and M. Zhou
Expression and Regulation of Bcl-2, Bcl-xl, and Bax Correlate With p53 Status and Sensitivity to Apoptosis in Childhood Acute Lymphoblastic Leukemia
Blood, April 15, 1997; 89(8): 2986 - 2993.
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V. N. Ivanov and V. N. Ivanov
Transcription Factor Activation during Signal-induced Apoptosis of Immature CD4+CD8+ Thymocytes. A PROTECTIVE ROLE OF c-Fos
J. Biol. Chem., March 28, 1997; 272(13): 8558 - 8566.
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BloodHome page
P. Zhou, L. Qian, K. M. Kozopas, and R. W. Craig
Mcl-1, a Bcl-2 Family Member, Delays the Death of Hematopoietic Cells Under a Variety of Apoptosis-Inducing Conditions
Blood, January 15, 1997; 89(2): 630 - 643.
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H. Matsuo, T. Maruo, and T. Samoto
Increased Expression of Bcl-2 Protein in Human Uterine Leiomyoma and Its Up-Regulation by Progesterone
J. Clin. Endocrinol. Metab., January 1, 1997; 82(1): 293 - 299.
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P. L. Simonian, D. A.M. Grillot, D. W. Andrews, B. Leber, and G. Nunez
Bax Homodimerization Is Not Required for Bax to Accelerate Chemotherapy-induced Cell Death
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K Wang, X M Yin, D T Chao, C L Milliman, and S J Korsmeyer
BID: a novel BH3 domain-only death agonist.
Genes & Dev., November 15, 1996; 10(22): 2859 - 2869.
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E. D. Bullock and E. M. Johnson Jr.
Nerve Growth Factor Induces the Expression of Certain Cytokine Genes and bcl-2 in Mast Cells. POTENTIAL ROLE IN SURVIVAL PROMOTION
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A. Srinivasan, L. M. Foster, M.-P. Testa, T. Ord, R. W. Keane, D. E. Bredesen, and C. Kayalar
Bcl-2 Expression in Neural Cells Blocks Activation of ICE/CED-3 Family Proteases during Apoptosis
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P. L. Simonian, D. A.M. Grillot, R. Merino, and G. Nunez
Bax Can Antagonize Bcl-XL during Etoposide and Cisplatin-induced Cell Death Independently of Its Heterodimerization with Bcl-XL
J. Biol. Chem., September 13, 1996; 271(37): 22764 - 22772.
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S. L. Gaffen, S. Y. Lai, M. Ha, X. Liu, L. Hennighausen, W. C. Greene, and M. A. Goldsmith
Distinct Tyrosine Residues within the Interleukin-2 Receptor beta Chain Drive Signal Transduction Specificity, Redundancy, and Diversity
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D. E. Bredesen
REVIEW {blacksquare} : Keeping Neurons Alive: The Molecular Control of Apoptosis (Part II
Neuroscientist, July 1, 1996; 2(4): 211 - 216.
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N. Shiraiwa, N. Inohara, S. Okada, M. Yuzaki, S.-i. Shoji, and S. Ohta
An Additional Form of Rat Bcl-x, Bcl-xbeta , Generated by an Unspliced RNA, Promotes Apoptosis in Promyeloid Cells
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W. Meikrantz and R. Schlegel
Suppression of Apoptosis by Dominant Negative Mutants of Cyclin-dependent Protein Kinases
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Genes Dev.Home page
S Shaham and H R Horvitz
Developing Caenorhabditis elegans neurons may contain both cell-death protective and killer activities.
Genes & Dev., March 1, 1996; 10(5): 578 - 591.
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DevelopmentHome page
G Middleton, G Nunez, and A. Davies
Bax promotes neuronal survival and antagonises the survival effects of neurotrophic factors
Development, January 2, 1996; 122(2): 695 - 701.
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S. Shankar, A. Kavanaugh-Black, S. Kamath, and A. M. Chakrabarty
Characterization of a Phosphoprotein Phosphatase for the Phosphorylated Form of Nucleoside-diphosphate Kinase from Pseudomonas aeruginosa
J. Biol. Chem., November 24, 1995; 270(47): 28246 - 28250.
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Arch DermatolHome page
C. R. J. Morales-Ducret, M. v. d. Rijn, and B. R. Smoller
bcl-2 Expression in Melanocytic Nevi: Insights Into the Biology of Dermal Maturation
Arch Dermatol, August 1, 1995; 131(8): 915 - 918.
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