<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Dynamic Modeling of the JAK2/STAT5 Signal Transduction Pathway to Dissect the Specific Roles of Negative Feedback Regulators"^^ . "Erythropoietin (Epo) acts as the key regulator of red blood cell development in mammals. During erythropoiesis, Epo initiates the JAK2/STAT5 signal transduction pathway that elicits pro-survival signals in erythroid progenitor cells. Therefore, the tight regulation of JAK2/STAT5 signaling is crucial for the fine-tuned balance of erythrocyte production. Recently, several factors regulating Epo-induced JAK2/STAT5 signaling have been identified. However, their relative contribution in controlling the dynamic behavior of JAK2/STAT5 signaling is poorly understood. To elucidate the specific roles of these negative regulators in attenuating the pathway, data-based mathematical modeling was employed. In this study, standardized protocols were established facilitating the generation of quantitative time-resolved data of Epo-induced JAK2/STAT5 pathway activation in primary erythroid progenitor cells and the hematopoietic cell line BaF3-EpoR, which is a frequently used model system to study EpoR signaling. For the fine-tuned overexpression of negative regulators in hematopoietic cells, an inducible Tet-On retroviral vector system was developed. Systematic comparison of stoichiometries and activation dynamics of Epo-induced JAK2/STAT5 signaling in CFU-E and BaF3-EpoR cells revealed fundamental differences between both cell types, emphasizing the importance of the use of primary cells in the investigation of EpoR signaling. Genome-wide expression profiling identified potential feedback regulators of Epo-induced JAK2/STAT5 signaling in CFU-E cells. To dissect the complex roles of negative regulators that employ different mechanisms to attenuate JAK2/STAT5 signaling, a data-based dynamic pathway model was established. Calibration of the mathematical model was performed using multiple experimental data sets of Epo-induced JAK2/STAT5 signaling monitored under different conditions. The estimated parameters were fully identifiable and displayed small confidence intervals, which are required for accurate simulations. Comprehensive model analysis identified the rapid recruitment of the phosphatase SHP-1 as major mechanism controlling the early-phase kinetics of pathway activation, while the two transcriptionally induced regulators SOCS3 and CIS were elucidated as modulators of the STAT5 steady-state phosphorylation level. Furthermore, global sensitivity analysis uncovered the concentrations of SHP-1 and JAK2 as well as the parameter SOCS3 expression as critical to control the integral signal strength of nuclear phosphorylated STAT5, which is proportionally linked to the survival of erythroid progenitor cells. In conclusion, by combining mathematical modeling with experimental data, the crucial regulators enabling the tight control of Epo-induced JAK2/STAT5 signaling were elucidated. The detailed understanding of the molecular processes and regulatory mechanisms of Epo-induced signaling during normal erythropoiesis can be further exploited to gain insights into alterations promoting erythroleukemia and related malignant hematopoietic diseases. "^^ . "2009" . . . . . . . . "Julie"^^ . "Bachmann"^^ . "Julie Bachmann"^^ . . . . . . "Dynamic Modeling of the JAK2/STAT5 Signal Transduction Pathway to Dissect the Specific Roles of Negative Feedback Regulators (PDF)"^^ . . . "DissertationBachmann.pdf"^^ . . . "Dynamic Modeling of the JAK2/STAT5 Signal Transduction Pathway to Dissect the Specific Roles of Negative Feedback Regulators (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Dynamic Modeling of the JAK2/STAT5 Signal Transduction Pathway to Dissect the Specific Roles of Negative Feedback Regulators (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Dynamic Modeling of the JAK2/STAT5 Signal Transduction Pathway to Dissect the Specific Roles of Negative Feedback Regulators (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Dynamic Modeling of the JAK2/STAT5 Signal Transduction Pathway to Dissect the Specific Roles of Negative Feedback Regulators (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Dynamic Modeling of the JAK2/STAT5 Signal Transduction Pathway to Dissect the Specific Roles of Negative Feedback Regulators (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #9241 \n\nDynamic Modeling of the JAK2/STAT5 Signal Transduction Pathway to Dissect the Specific Roles of Negative Feedback Regulators\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .