Charakterisierung der Regulation und Funktion von PPARbeta

During the last years increasing data has arisen that a group of nucelar hormone receptors, the PPARs (peroxisome proliferator activated receptors), might play an important role in processes like cell cycle, apoptosis or angiogenesis. The family of PPARs exist of three ligand-inducible trancription factors (PPARalpha, PPARbeta and PPARgamma) that are regulated by fatty acids and their derivatives. Prostacyclin, a major arachidonic acid derived cyclooxygenase metabolit, has often been desribed as an agonist of PPARbeta. Surprisingly the different data shown here, doesn't confirm this. For instance, the 4-hydroxytamoxifen mediated activation of a cRaf-estrogen receptor fusion protein led to the induction of both the PPARbeta and Cox-2 genes, concomitant with a dramatic increase in prostacyclin synthesis. However, 4-OH-tamoxifen failed to activate PPARbeta transcriptional activity, indicating that prostacyclin is insufficient for PPARbeta activation. In agreement with this conclusion, the overexpression of ectopic Cox-2 and prostacyclin synthase resulted in massive prostacyclin synthesis but did not activate the transcriptional activity pf PPARbeta. The second part of the work describes the characterisation of putative target genes of PPARbeta. The combination of siRNA technology, microarray analysis and real-time pcr revealed at least two promising candidate target genes, that might play a role in PPARbeta-driven angiogenesis during the development of certain tumors.