Molecular Mechanism Of The Role Of Ppargamma And Rxralpha In Bladder Carcinogenesis
Reference : PhD Natacha ROCHEL
Offer publication : April 5, 2016
The peroxisome-proliferator-activated receptors, PPARs are non-steroidal nuclear receptors that are ligand-dependent transcription factors controlling a multitude of physiological phenomena. They are found in the nucleus bound to their hormone responses elements on target DNA, as heterodimers with the retinoid X receptor (RXR). The 3 isotypes of PPARs (PPARa, PPARb/d and PPARg) have critical roles in energy metabolism, and regulate diverse processes such as development, differentiation and inflammation. While PPARg has mainly been shown to be involved in adipogenesis and glucose homeostasis, more recent data indicate anti-proliferative and differentiation functions of PPARg notably it regulates
urothelial differentiation. The role of PPARg in tumorigenesis is complex. It has mainly been described as tumor suppressor but recent evidence suggested that it could display an unexpected protumorigenic role in bladder cancer. Hypothesis of a protumorigenic role of PPARgin bladder cancer was raised with the observed increased incidence of bladder cancer after anti-diabetic treatments based on PPARgagonists and reinforced by the identification of a PPARg activation transcriptomic signature in bladder tumors.
The goal of the project is to analyze by using an integrative biology approach, the molecular mechanisms of the regulation of transcription by PPARg and RXRa and to identify the mechanisms involved in PPARg-RXRa protumorigenic activities in bladder cancer. This project will be conducted in close
collaboration with the team of F. Radvanyi (Institut Curie) who characterizes functionally the roles of these nuclear receptors in bladder cancer.
With this project, we aim at :
(i) Characterizing the signaling pathways controlled by PPARG-RXRA complex in bladder differentiated tumors.
(ii) Characterizing the changes in PPARG receptor structure/activity induced by mutations, DNA and coactivator binding and identifying ligands that modulate this structure/activity.
- WISHED SKILLS : Basal education in molecular, cellular and/or structural biology as well as a strong motivation for fundamental questions in biology are required. The project is making use of numerous techniques: expression, purification and biochemical, structural and functional characterization of macromolecular complexes. This project will also deal with in vivo analyses in mammalian cells.
- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : The PhD candidate will use and learn a combination of several very complementary approaches involving molecular biology, cell biology, biochemistry, bioinformatics (for ChIP seq), chacterization of complexes by biophysical methods and structural methods (X-ray crystallography, Small Angle X-ray Scattering and cryo-EM).
Application Deadline : Dec. 31, 2016