Recruitment of Nuclear Receptor Corepressor and Coactivator to the Retinoic Acid Receptor by Retinoid Ligands

Abstract

Ligand activation of retinoic acid receptors (RARs) involves coordinated changes in their interaction with coregulatory molecules. Binding of the agonist all-transretinoic acid to the RAR results in increased interaction with coactivator molecules as well as a decreased interaction with corepressor molecules. Thus, an all-transretinoic acid antagonist might function either by preventing agonist induction of such events or, additionally, by actively increasing repression via corepressor recruitment. We demonstrate that the repression of the transcriptional activity of a constitutively active RAR␥-VP-16 chimeric receptor by the inverse agonist AGN193109 requires a functional Co-R box and that binding of this ligand to RAR␥ leads to an increased interaction with the corepressor N-CoR both in glutathione S-transferase pull-down and yeast two-hybrid analyses. Detection of nuclear receptor corepressor (N-CoR) association with RAR␥ was greatly facilitated by inclusion of a RARE oligonucleotide in coimmunoprecipitation analyses, a result of an increase in association of the ternary complex consisting of RAR, RXR, and DNA. Similarly, this DNA-dependent increase in heterodimer formation likewise resulted in an increase in agonistmediated recruitment efficiency of the coactivator SRC-1. Under conditions which favor ternary complex formation, a RAR neutral antagonist is distinguished from an inverse agonist with respect to corepressor recruitment as is a RAR partial agonist distinguished from an agonist with respect to coactivator recruitment. These results indicate that it is possible to design RAR ligands with distinct recruitment capabilities for coregulators, both coactivators as well as corepressors. In addition, using this recruitment assay, we show that SRC-1 and the related coactivator molecule ACTR associate with the ternary complex via utilization of different helical motifs within their conserved receptor interaction domains.

E3 ligase FLRF (Rnf41) regulates differentiation of hematopoietic progenitors by governing steady-state levels of cytokine and retinoic acid receptors

“…The RA functions through RARα and RXR receptors, which act as ligand-inducible transcription factors, and interact with specific DNA targets as heterodimers (RAR-RXR) or homodimers (RXR-RXR) [40][41][42]. We have confirmed previously published observation [24] that treatment with RA enhances IL-3 or GM-SCF-induced differentiation of wt EML cells into CFU-GM progenitors (Fig.…”

Oct-1 Preferentially Interacts with Androgen Receptor in a DNA-dependent Manner That Facilitates Recruitment of SRC-1

“…In addition, the POU factor Pit-1 interacts with the coactivator CBP/p300, which is itself recruited by SRC-1 (59). Furthermore, it was recently reported that a DNA-dependent retinoic acid receptor/retinoid X receptor interaction increases SRC-1 recruitment in a ligand-dependent manner (60). This study also demonstrated that retinoic acid receptor binding to a DR5 retinoic acid response element facilitates recruitment of the corepressor N-CoR in coimmunoprecipitation assays.…”

A Structural Model of the Constitutive Androstane Receptor Defines Novel Interactions That Mediate Ligand-Independent Activity

“…These molecular events further highlight the reversed transcriptional properties of CAR, as ligand for classical receptors performs the exact opposite function, i.e., corepressor displacement and coactivator recruitment. It is interesting that corepressors were initially identified for their ability to repress basal transcription in unliganded or antagonist-occupied receptors (26). Subsequent studies demonstrated that certain estrogen receptor antagonists could recruit corepressors without significantly lowering basal transcriptional activity (24,29,44).…”