<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Kinetic design of the JAK-STAT1 pathway\r\nand MYCN impact on cell cycle decisions in neuroblastoma"^^ . "We utilized the framework of mathematical modeling to gain insights into two distinct biological systems, the JAK/STAT1 signal transduction pathway and the regulation of cell cycle decisions in neuroblastoma.!! The family of JAK/STAT signaling pathways plays a key role in immunity. In several tumors dysregulation of the JAK/STAT pathways is observed. To investigate the functionality of this signal transduction pathway and eventually understand basic building principles, we establish a databased mathematical model of the JAK/STAT1 pathway by means of kinetic rate equations. We showed that pathway activation is coupled tightly to the receptor stimulus at the cost of signal strength. The nuclear signal is sustained by a combination of fast translocation rates and short nuclear residence times of activated STAT1 protein molecules. Model simulations reveal that STAT1 dimerization kinetics have a strong impact on both efficiency of signaling and response kinetics, implying that protein-protein interactions are evolutionary constrained to ensure network functionality. Measurements of STAT1 transport mutants validated the mathematical model and showed that STAT1 activation is robust against enhanced nuclear export. By the kinetic design of the pathway input noise is suppressed, the pathway can be efficiently activated and rapid relaxation after stimulus withdrawal is ensured.!!\r\nNeuroblastoma is the most common extracranial solid tumor of infants and children. Its course of illness varies between spontaneous regression and malignant, aggressive progression. Amplification of the MYCN oncogene is predictive for poor clinical outcome in neuroblastoma. MYCN-amplified cells proliferate strongly and exhibit impaired cell cycle arrest. To rationalize the impact of MYCN on the regulatory networks, governing cell cycle progression and DNA damage response, we established mathematical models of the regulatory modules, p53-MDM2 and E2F1-pRB, by means of mass action kinetics. The inherent regulation in the p53-MDM2 module leads to an universal form of the p53- MDM2 steady state and can account for several qualitatively different behaviors upon p53 activation. We show that it is plausible that the weak G1 arrest in the MYCN- overexpressing cells is due to a MYCN-induced protein level imbalance in the p53- MDM2 module. Furthermore we argue that the bifurcation diagram of the G1-S transition model can both theoretically as well as experimentally be used as an output to analyze the restriction point behavior in neuroblastoma. It shows that for cells with relatively high MYCN level and an enhanced CDK4 signal the bistable region is shifted to low stimuli and the model stays in an activated state even under DNA damage. A mathematical framework is provided, which potentially can serve as a future standard method to extract underlying cell cycle parameters from combined FACS-measured cell cycle phase distributions and cell growth rate measurements. Analysis of measurements in the SH-EP neuroblastoma cell line showed that conditionally upregulated MYCN mainly changes the length of the G1 phase."^^ . "2012-12-18" . . . . . . . "Florian"^^ . "Lamprecht"^^ . "Florian Lamprecht"^^ . . . . . . "Kinetic design of the JAK-STAT1 pathway\r\nand MYCN impact on cell cycle decisions in neuroblastoma (PDF)"^^ . . . "finalThesisFLamprecht.pdf"^^ . . . "Kinetic design of the JAK-STAT1 pathway\r\nand MYCN impact on cell cycle decisions in neuroblastoma (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Kinetic design of the JAK-STAT1 pathway\r\nand MYCN impact on cell cycle decisions in neuroblastoma (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Kinetic design of the JAK-STAT1 pathway\r\nand MYCN impact on cell cycle decisions in neuroblastoma (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Kinetic design of the JAK-STAT1 pathway\r\nand MYCN impact on cell cycle decisions in neuroblastoma (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Kinetic design of the JAK-STAT1 pathway\r\nand MYCN impact on cell cycle decisions in neuroblastoma (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #14277 \n\nKinetic design of the JAK-STAT1 pathway \nand MYCN impact on cell cycle decisions in neuroblastoma\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . .