Posttranskriptionale Veränderungen der E3-Ubiquitin-Ligase IMP (impedes mitogenic signal propagation)

Post-transcriptional modifications of E3-Ubiquitin-Ligase IMP (impedes mitogenic signal propagation)

by Christian Böcker
Doctoral thesis
Date of Examination:2013-08-26
Date of issue:2013-10-08
Advisor:PD Dr. Tim Seidler
Referee:Prof. Dr. Jürgen Wienands
Referee:Prof. Dr. Rainer Mausberg
Persistent Address: http://dx.doi.org/10.53846/goediss-4038

 

 

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Abstract

English

The ERK1/2 cascade is associated with determining cellular processes like cell growth, differentiation, cell division and apoptosis. Furthermore it is awarded with an essential role in cardiac hypertrophy. It was shown that Impedes Mitogenic Signal Propagation (IMP) acts as a steady-state resistor within the Raf-MEK-ERK kinase module by inhibiting the signal transduction mediated by RAF to MEK. In preliminary works the importance of IMP could be shown in view of the development of heart hypertrophy and a myocardium infarction. In the present work the meaning of posttranscriptional modifications of IMP was examined in COS-7 cells. The investigations grounded on the IMP provided inhibition of the ERK1/2 cascade on height of the MAPK (K) that were characterized with the interaction between B-RAF and MEK or with the interaction between constitutive active c-RAFBXB and MEK in the Mammalia Two hybrid system. We showed a comparable inhibition by IMP for the c-RAFBXB as well as for the B-RAF dependent MEK activation. In contrast to wild type-IMP this regulatory influence was kept with the investigation of the nonubiquitinylatable mutant IMPC264A in COS-7 cells stimulated by RASV12. These findings are in line with a published mechanism of a RAS dependent auto ubiquitinylation and degradation of IMP. For the investigation of the potential phosphorylationsides nonphosphorylatable mutants were produced and characterised in the Luciferase-Assay. With these results we could show that the influence by IMP on the ERK1/2 cascade is adjustable by phosphorylation in the positions T308 and S574.
Keywords: impedes mitogenic signal propagation; IMP; mitogen activated protein kinase; RAF; MEK; ERK; MAPK; post-transcriptional modifications
 
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