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J Biol Chem, Vol. 274, Issue 32, 22165-22169, August 6, 1999
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From the Erythropoietin (Epo) initiates its cellular
response by binding to the Epo receptor, which triggers the activation
of signal transducer and activator of transcription (Stat) 5 protein.
Cell culture studies of erythroid progenitors have suggested that Epo functions as a survival factor by repressing apoptosis at least in part
through Bcl-xL, an anti-apoptotic protein of the
Bcl-2 family. In this report, we examine whether Stat5 can induce
transactivation of the bcl-x gene in response to Epo. Two
Epo-responsive progenitor cell lines, HCD-57 and Bcl-2-transfected
Ba/F3-Epo receptor (Ba/F3-EpoR-Bcl-2), were used in this study. After
Epo stimulation, we observed a correlation between expression of
bcl-xL and activation of Stat5 as assessed by the
expression of oncostatin M, a direct target of
Stat5, and the phosphorylation and nuclear translocation of Stat5.
Moreover, a Stat binding element in the bcl-x promoter was
found to be active in response to Epo, a finding that was further
confirmed because mutagenesis of this sequence motif abrogated its
promoter activity and overexpression of a dominant negative Stat5
protein blocked transactivation. When DNA-protein binding analyses were
performed, we found that Stat5, not Stat1 or Stat3, was the protein
bound to the bcl-x promoter in response to Epo. These data
suggest that Epo-dependent activation of Stat5 is a transcriptional pathway that can be used by Epo-responsive progenitor cells to induce the expression of bcl-xL
and consequently to inhibit apoptosis.
Servicio de Inmunologia, Hospital
Universitario Marques de Valdecilla, INSALUD, 39008 Santander, Spain,
Departamento de Hematologia y Oncologia Medica, Hospital Clinico
Universitario, 46010 Valencia, Spain, and ** Department of Pathology,
University of Michigan Medical School, Ann Arbor, Michigan 48109
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M. L. Brines, P. Ghezzi, S. Keenan, D. Agnello, N. C. de Lanerolle, C. Cerami, L. M. Itri, and A. Cerami From the Cover: Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury PNAS, September 12, 2000; 97(19): 10526 - 10531. [Abstract] [Full Text] [PDF]
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 M. Horita, E. J. Andreu, A. Benito, C. Arbona, C. Sanz, I. Benet, F. Prosper, and J. L. Fernandez-Luna Blockade of the Bcr-Abl Kinase Activity Induces Apoptosis of Chronic Myelogenous Leukemia Cells by Suppressing Signal Transducer and Activator of Transcription 5-dependent Expression of Bcl-xL J. Exp. Med., March 13, 2000; 191(6): 977 - 984. [Abstract] [Full Text] [PDF]
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 M. Kieslinger, I. Woldman, R. Moriggl, J. Hofmann, J.-C. Marine, J. N. Ihle, H. Beug, and T. Decker Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation Genes & Dev., January 15, 2000; 14(2): 232 - 244. [Abstract] [Full Text]
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G. B. Ehret, P. Reichenbach, U. Schindler, C. M. Horvath, S. Fritz, M. Nabholz, and P. Bucher DNA Binding Specificity of Different STAT Proteins. COMPARISON OF IN VITRO SPECIFICITY WITH NATURAL TARGET SITES J. Biol. Chem., February 23, 2001; 276(9): 6675 - 6688. [Abstract] [Full Text] [PDF]
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H. Sakamoto, T. Kitamura, and A. Yoshimura Mitogen-activated Protein Kinase Plays an Essential Role in the Erythropoietin-dependent Proliferation of CTLL-2 Cells J. Biol. Chem., November 10, 2000; 275(46): 35857 - 35862. [Abstract] [Full Text] [PDF]
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T. J. Pircher, J. N. Geiger, D. Zhang, C. P. Miller, P. Gaines, and D. M. Wojchowski Integrative Signaling by Minimal Erythropoietin Receptor Forms and c-Kit J. Biol. Chem., March 16, 2001; 276(12): 8995 - 9002. [Abstract] [Full Text] [PDF]
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A. Masuda, T. Matsuguchi, K. Yamaki, T. Hayakawa, and Y. Yoshikai Interleukin-15 Prevents Mouse Mast Cell Apoptosis through STAT6-mediated Bcl-xL Expression J. Biol. Chem., July 6, 2001; 276(28): 26107 - 26113. [Abstract] [Full Text] [PDF]
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