Regulation der Transkription durch PPARβ/δ in Zelltypen des Tumorstroma

Der Peroxisomen-Proliferator aktivierte Rezeptor β (PPARβ) ist ein Liganden-induzierter Transkriptionsfaktor. PPARβ spielt eine wichtige Rolle im Lipidmetabolismus und bei der Energiehomöostase, weiterhin übernimmt er eine regulatorische Funktion bei der Zelldifferenzierung, Proliferation und Apopto...

Full description

Saved in:
Bibliographic Details
Main Author: Rieck, Markus
Contributors: Müller-Brüsselbach, Sabine (Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2008
Online Access:PDF Full Text
Tags: Add Tag
No Tags, Be the first to tag this record!

Peroxisome proliferator-activated receptor β (PPARβ) is a ligand-induced transcription factor. PPARβ plays essential roles in lipid metabolism and energy homoeostasis and has important functions in the regulation of cell proliferation, differentiation and apoptosis. Additionally, previous work of our group unravelled an unexpected role in tumour angiogenesis. The genetic disruption of the Pparb gene leads to tumour endothelial hyperplasia and deregulation of tumour angiogenesis. As a consequence syngeneic lewis lung tumour growth is impaired in Pparb-deficient mice. In the present thesis it could be shown that the retroviral transduction of PPARβ triggers microvessel differentiation and maturation in an in vivo model system (matrigel). Several potential PPARβ target genes were previously identified in the same model. As part of the present work, the PPARβ responsiveness of these target genes was validated and characterised in various cell culture systems (genetic disruption, reexpression and RNAi knockdown of Pparb). In addition to the known regulators of angiogenesis Cd36 and Thbs2, we identified the Cdkn1c gene encoding the cell cycle inhibitor p57KIP2 as a PPARβ target gene. Furthermore, a functional connection between PPARβ and p57KIP2 in the regulation of fibroblast proliferation could be demonstrated. In the second part of this work, the influence of ligands and intracellular fatty acid transport proteins on the transcriptional activity of the PPARβ receptor has been analysed. All trans-retinoic acid (atRA) has recently been reported to act as a ligand for PPARβ, to activate its transcriptional activity and, in contrast to the “classical” function of atRA, to stimulate cell proliferation. In contrast to these findings, results of the present work rule out a direct activation of PPARβ and its target genes by atRA. Additionally, no influence of the fatty acid binding protein 5 (FABP5) on transcriptional activity of PPARβ could be detected. The third part of this work addressed the question as to whether PPARβ is post-translational modified by ubiquitin or SUMO, as previously reported for PPARα and / or PPARγ. In the present thesis, SUMOylation of PPARβ was undetectable, whereas modification by ubiquitination and degradation by the 26S-proteasome system could be clearly demonstrated. Additionally, a stabilising influence of ligand-binding was seen only under conditions of PPARβ overexpression, which might serve as a safeguard mechanism protecting the cell from deregulated PPARβ expression under certain pathophysiological conditions.