Regulation of transcription and degradation of PPARgamma and RXR by the ubiquitin-proteasome system

• Applicant: Dr. Stefanie Hauser
• Subject Area: Cell Biology
• Term: from 2001 to 2006
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5352180

My proposal is focussed on a protein called PPAR-gamma that is involved in the regulation of type 2 diabetes mellitus, in cancer biology and inflammatory processes. PPAR-gamma is a transcription factor whose activity can be induced by certain drugs. I have shown recently that these drugs not only lead to the activation of PPAR-gamma but also to its degradation. It now appears that the activation and degradation processes are intimately linked to each other. Even though synthetic drugs that activate PPAR-gamma can be used for the treatment of type 2 diabetes, they are not powerful enough to completely normalize blood sugar levels. We therefore want to investigate whether the processes of activation and degradation of PPAR-gamma can be separated. In order to address this question we will investigate the molecular mechanisms that lead to the degradation of PPAR-gamma. If the events were separable, one might be able to design more powerful drugs that lead to PPAR-gamma activation without its degradation. Since PPAR-gamma plays a role in many biological processes, we want to determine how the activation of its targets is regulated. This knowledge would help to focus the response to PPAR-gamma activation to the processes required for a certain therapy.

• DFG Programme: Research Grants