Retinoic acid receptor transcriptional corepressor

Thyroid hormone, 1,25-dihydroxy vitamin D, and retinoic acid receptor regulation of transcription. The hormone receptor (HR) is dimerized at site (3) and is bound to DNA at hormone response element site (2). Without the ligand, transcription is inactive due to the interaction of HR with corepressor at site 4. When the ligand (hormone) binds to HR, the bound corepressor dissociates leading to an interaction between the coactivator and HR. These regulatory changes result in increased transcription. 

Recently, this system was used to identify several factors putatively involved in the mechanism of steroid hormone-mediated gene transcription. In a two-hybrid screen to identify factors that interact with the vitamin D receptor (VDR), we isolated transcription factor IIB (TFIIB) as a VDR-mteractive clone (2). The interaction of VDR, retinoic-acid receptors and other steroid-hormone receptors with TFIIB may represent a fundamental step in the mechanism of transcription mediated by the nuclear-receptor family (3-5) The two-hybrid system has also identified several putative coactivator and corepressor proteins that contact retinoid receptors, thyroid receptors, vitamin D receptors, and other members of the nuclear-receptor family (6-9) Thus, the two-hybrid system is playing an instrumental role in the identification of factors involved in nuclear receptor-mediated gene expression This chapter discusses several procedures and strategies used to establish a two-hybrid system to examine proteins that interact with retinoid receptors, with the VDR, or with nuclear receptors in general. 

Beside coactivators so-called corepressors exist that are bound to transcription factors such as nuclear receptors and inhibit the initiation of transcription. These factors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), which interact with nuclear receptors and serve as platforms for complexes containing histone deacetylases (HDACs). These enzymes cause the reversal of histone acetylation of histones leading to a tightening of chromatin and enhancing its inaccessibility for RNA polymerase containing complexes. 

When bound to a response element, the vitamin A-dependent nuclear receptors are able to interact with coactivators and corepressors present in the nucleus either to stimulate or to repress transcriptional activity. Interactions with coactivators or corepressors will result respectively in transcriptional activation or repression. Thus, retinoic acid availability as a ligand for binding to RARs and/or RXRs and the ability of these receptors to bind alternatively to either coactivators or corepressors provides a mechanism through which genes can be either activated or repressed by retinoic acid. It is this gene regulatory mechanism that accounts for the great majority of vitamin A action in the body. 

---