Activation of STAT5 during EPO-directed suppression of apoptosis.
The ligand-dependent activation of the JAK/STAT (Januskinase/Signal Transducer and Activator of Transcription) pathway has been implicated in the explanation of cytokine-specific regulation of gene expression. Previous studies have reported conflicting results on the role of the transcription factor STAT5 in erythropoietin (EPO)-induced cellular responses. In this study we focused on the functional importance of STAT5 docking sites in the intracellular EPO receptor (EPOR) domain for the mediation of antiapoptotic activities. We demonstrate that EPO-dependent survival of erythroleukemic cell lines is accompanied by sustained STAT5 DNA-binding activity. The role of single tyrosine residues was dissected by the analysis of myeloid FDCP-1 cells stably expressing mutant EPOR proteins. The data show that receptors having a high potential to mediate antiapoptotic signals also effectively activate STAT5, whereas receptors lacking STAT5 docking sites are diminished in both activities. We conclude that the transcription factor STAT5 is functionally implicated in the EPO-dependent survival of cells.
Bittorf
T
T
Institute of Medical Biochemistry, Medical Faculty, University of Rostock, Germany. thomas.bittorf@med.uni-rostock.de
Seiler
J
J
Lüdtke
B
B
Büchse
T
T
Jaster
R
R
Brock
J
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004900:Erythroblasts / Q000378:metabolism* / Q000473:pathology*; D004921:Erythropoietin / Q000494:pharmacology*; D004915:Leukemia, Erythroblastic, Acute; D051379:Mice; D008894:Milk Proteins; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D004921:Erythropoietin