Retinoic acid receptors (RARs) are ligand-dependent transcription factors that regulate diverse aspects of development and homeostasis by binding to response elements in target genes as heterodimers with retinoid X receptors (RXRs). Although several lines of evidence support a critical role of RARs in controlling the development of myeloid cells, the mechanisms by which RARs activate or repress transcription so as to regulate complex developmental programs are not understood. The objectives of this proposal are to identify and characterize proteins that mediate the transcriptional activities of RARs during myeloid development. Our recent studies of RAR/RXR heterodimers have led to the discovery that receptor-receptor and receptor-DNA interactions play important roles in regulating the transcriptional outcomes to RAR and RXR-specific ligands. The major hypothesis of this proposal is that transcriptional activation and repression by RAR is mediated through distinct co-activator and co-repressor proteins that interact with nuclear receptor heterodimers in a manner that is controlled by ligand, heterodimer composition and organization of the DNA binding Site. We have recently identified a 270 kDa protein, termed N-CoR, that mediates transcriptional repression by unliganded RAR. Several proteins have also been identified that interact with the ligand-dependent activation function of RAR and represent putative co-activator proteins. We propose to characterize these proteins and examine their roles in mediating the biological actions of normal and mutant RARs during myeloid cell development. Studies proposed in AIM 1 will examine the mechanisms by which ligand binding, dimerization and DNA binding control the interactions of RXR heterodimers with co-activators and co-repressors.
In AIM 2, studies are proposed to examine potential mechanisms by which N-CoR functions as a co-repressor. The goal of AIM 3 will be to determine the role of N-CoR in mediating the actions of normal and mutant RARs during the differentiation of myeloid progenitor cells. Studies proposed in AIM 4 will be directed at the cloning and characterization of coactivator proteins that are required for positive regulation of gene expression in hematopoietic cells. Insights derived from these studies are likely to lead to an improved understanding of the mechanisms by which retinoic acid receptors positively and negatively regulate gene expression.
Showing the most recent 10 out of 32 publications
