Project Details
Projekt
Regulation of the ubiquitin-proteasome-system during oxidative stress
Applicant
Professor Dr. Tilman Grune
Subject Area
Biochemistry
Term
from 2000 to 2006
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 5249904
Many environmental toxicants, medical drugs, and abuse substances exert their toxic effects via oxygen free radicals and related active oxygen species. Despite extensive work on lipid peroxidation little is known about protein oxidation and the possible regulation of proteolytic enzymes, responsible for degradation of these oxidized proteins. Our objective is to test the regulation of the proteasomal system and the interaction of oxidized proteins with the ubiquitination system.Although it seems to be established, that the proteasomal system degrades oxidized cytosolic proteins, the mechanism of recognition by the ubiquitin system is still not known. It was found by several groups that the 20S proteasome can recognize oxidized proteins and degrade them preferentially in in vitro systems. On the other hand in living cells the major protease degrading intracellular proteins is the 26S proteasome. Since this proteasomal form is able to recognize and degrade polyubiquitinated proteins it is interesting to know the recognition signals of oxidized proteins by the ubiquitination system. Therefore, oxidized proteins and model substrates will be used as substrates for ubiquitination assays and by using of oxidation markers the selective recognition is investigated. It was demonstrated, that besides the possible interactions of the ubiquitinating enzymes with the substrate a modulation of the proteasome itself occurs during oxidative stress. The binding of the major regulators, like the 11S and the 19S particles to the 20S core proteasome will be investigated during and after oxidative stress together with other regulatory mechanisms of the proteasome. Therefore, the proposal is focused on the function and regulation of the proteasomal and the ubiquitination system of mammalian cells and seems to fulfill the criteria of the program "Structure, function and regulation of the 20S/26S ubiquitin-proteasome system".
DFG Programme
Priority Programmes
