Összes szerző

Lina Fadel

az alábbi absztraktok szerzői között szerepel:

Lina Fadel
Impact of agonist treatment on RXR partner selection

Aug 26 - hétfő

09:40 – 09:55

Sejtanalitika biofizikai megközelítéssel

E6

Impact of agonist treatment on RXR partner selection

Lina Fadel1, Laszlo Nagy2,3,4, György Vámosi1

1Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

2Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

3UD-Genomed, Debrecen, Hungary.

4Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine and Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA. lnagy@jhmi.edu.

Retinoid X Receptor (RXR) plays a pivotal role as a transcription regulator. It serves as an obligatory heterodimerization partner for many other nuclear receptors (NRs). Activation of RXR heterodimers exert a transcriptional activity controlling a wide variety of important biological processes such as development, differentiation, metabolism and cell death. NRs share a common structure composed of several functional domains: an N-terminal transcription activation function domain; a DNA-binding domain; a flexible hinge region domain; and a C-terminal ligand binding domain. The mechanism of activation called molecular switch is also common between these receptors. In this study we intended to understand how the promiscuous RXR molecule behaves in the presence of several potential heterodimeric partners and ligands. We hypothesized that there is a competition between RXR partners for binding to RXR and binding of a specific agonist increases the affinity of a given receptor to RXR. Our hypothesis was tested with three partners of RXR: PPARγ, RAR,VDR using nuclear translocation assay in a three-color model system. The competition was evaluated detecting changes in heterodimerization between RXR and one of its partners, NR1, in the presence of another competing partner, NR2. Therefore, NR1 was needed in a form that is distributed evenly in the cell when expressed alone and enriched in the nucleus when interacting with RXR. These conditions were fulfilled by wt. VDR and mutant forms of both PPARγ and RAR lacking their NLS. Our data revealed that RXR binds to its unliganded partners with different affinities; highest for RAR, lowest for VDR and moderate for PPARγ while specific agonist treatment tips the scale in favor of the liganded partner.

This work was undertaken to a better understanding of RXR partition between its different heterodimeric and to obtain insight into triggering specific signaling pathway in complicating cellular environments.