Retinoids exert pleiotropic effects on mammalian physiology. They play a key role in epithelial cell differentiation, have profound effects on limb and nervous system morphogenesis, are potent inhibitors of carcinogenesis, and are currently used as chemopreventive and therapeutic agents in several types of cancer. Signalling by these hormones is mediated by two classes of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) which bind all trans- and 9 cis-retinoic acids, respectively. These receptors usually associate with regulatory elements upstream from speCific target genes and act as ligand-inducible transcription factors. The proposed project is designed to clarify the factors that modulate the multiple interactions of retinoid nuclear receptors and obtain insights into the mechanisms by which signalling by retinoids may be regulated. The processes of self- association of receptor proteins and their interactions with their ligands and with cognate DNA will be studied. Binding affinities characterizing these interactions as well as the kinetic parameters leading to the formation of receptor-ligand-DNA complexes will be investigated using quantitative methods. The interactions of the retinoid X receptors with the thyroid hormone receptor will be studied to better understand the mechanisms by which signalling pathways by thyroid hormone and by retinoids may converge to affect gene transcription. To clarify one aspect of the mechanisms by which retinoids may suppress carcinogenesis, the interactions of retinoid receptors with the proton- oncogene products c-Fos and c-Jun (AP-1 transcription factor) and the effects of retinoid receptors on binding of the AP-1 factor to its cognate DNA will be investigated. The roles of post-translational modification of receptor proteins in modulating their various interactions will be examined in order to better understand the mechanisms underlying the regulation of retinoid receptor function in the cell.
Showing the most recent 10 out of 24 publications
