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Mitogen-activated protein kinase (MAPK) signaling determines crucial cell fate decisions in most cell types, and mediates cellular transformation in many types of cancer. The activity of MAPK is controlled by reversible phosphorylation, and the quantitative characteristics of MAPK activation determine the cellular response. | A systems biological approach suggests that transcriptional feedback regulation by dual-specificity phosphatase 6 shapes extracellular signal-related kinase activity in RAS-transformed fibroblasts Nils Bluthgen1 2 Stefan Legewie1 Szymon M. Kielbasa3 Anja Schramme2 Oleg Tchernitsa2 Jana Keil2 Andrea Solf2 Martin Vingron3 Reinhold Schafer2 Hanspeter Herzel1 and Christine Sers2 1 Institute for TheoreticalBiology Humboldt University Berlin Germany 2 Laboratory of Molecular Tumor Pathology Charite Universitatsmedizin Berlin Germany 3 ComputationalBiology Max Planck Institute for Molecular Genetics Berlin Germany Keywords dual-specificity phosphatase mathematical modelling mitogen activated protein kinase transcriptional feed-back Correspondence N. Bluthgen Institute of Pathology Universitatsmedizin Charite FORSYS junior group Chariteplatz 1 D-10117 Berlin Fax 49 30 450 536 909 Tel 49 30 450 536 134 E-mail nils.bluethgen@charite.de Database The mathematical model described here has been submitted to the Online Cellular Systems Modelling Database and can be accessed at http jjj.biochem.sun.ac.za data-base bluthgen index.htmlfree of charge Received 10 July 2008 revised 8 November 2008 accepted 8 December 2008 doi 10.1111 j.1742-4658.2008.06846.x Mitogen-activated protein kinase MAPK signaling determines crucial cell fate decisions in most cell types and mediates cellular transformation in many types of cancer. The activity of MAPK is controlled by reversible phosphorylation and the quantitative characteristics of MAPK activation determine the cellular response. Many systems biological studies have analyzed the activation kinetics and the dose-response behavior of the MAPK signaling pathway. Here we investigate how the pathway activity is controlled by transcriptional feedback loops. Initially we predict that MAPK signaling regulates phosphatases by integrating promoter sequence data and ontology-based classification of gene function. From this we deduce that MAPK signaling
