Retinoic Acid Receptor Assays

Overview of Retinoic Acid Receptor (RAR)

Retinoic acid (RA) regulates multiple important biological processes by activating the cognate nuclear receptor RAR. RAR is a nuclear hormone receptor that functions as a heterodimer with the retinoic acid X receptor (RXR). There are three distinct RAR isoforms: RARα, RARβ, and RARγ. RARα is highly expressed in many tissues, whereas RARβ and RARγ are more selectively expressed.

Function of RARs

RARs are mainly composed of a central DNA-binding domain (DBD) and a ligand-binding domain (LBD). RARs function as ligand-dependent transcriptional regulators. RARs play key roles in embryonic development, differentiation, and growth arrest. In addition, RARs are involved in regulating the growth and differentiation of adult cell types. Notably, RXRs also mediate pathological processes such as immunity, neurite outgrowth, and neurite regeneration.

Fig.1 Crystal structures of RARα with different ligands. Fig.1. Crystal structures of RARα with different ligands. (Noman, 2020)

Mechanisms of RARs

RARs mediate a wide variety of functions by participating in multiple signaling pathways.

Receptor	Gene	Mechanism	Agonists	Antagonists
RARα	RARA	RARα is central to cAMP-dependent parietal endoderm differentiation.	AM 580 AM 80 BMS 753	Selective RARα antagonist ER 50891 BMS 453
RARβ	RARB	RARβ may function as coactivators of the Smad pathway.	Adapalene AC 261066 CD 2314	CD 2665 LE 135
RARγ	RARG	RARγ activates PI3K/Akt and NF-κB signaling pathways. RARγ signals via the Wnt/β-catenin pathway.	Adapalene BMS 961 CD 1530 CD 437	CD 2665 LY 2955303 MM 11253 BMS 453

Published Data

Paper Title	Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer
Journal	Iscience
Published	2021
Abstract	RA signaling plays a crucial role in the regulation of cell proliferation and differentiation. In addition, disturbed RA signaling is closely linked to cancer initiation and progression. However, the relationship of RA signaling to intestinal homeostasis and disease progression is not fully understood. This article revealed the link between RAR and RXR activation and transcriptional enhancement of enterocyte-specific genes in mouse small intestinal organoids. Notably, inhibiting this pathway resulted in decreased expression of genes associated with the uptake lineage. Furthermore, the findings suggested that decreased expression of RXR target genes was strongly associated with poorer colorectal cancer (CRC) prognosis, implying that RA signaling could serve as a potential therapeutic target in CRC.
Result	This article revealed the close association of RA metabolism and RXR with differentiation-related gene expression in the mouse small intestine and human colon. In this study, they elucidated the regulatory role of RA signaling on the conserved differentiation of enterocyte lineages in the mouse small intestine and human colon organoids. This effect could be prevented by inhibiting RXR dimerization and is at least partially dependent on the permissive chromatin structure. Furthermore, the combination of these findings with gene expression data from CRC patients revealed that disruptions in RXR-dependent differentiation induction are associated with poor prognosis. This demonstrated the clinical relevance of these findings and indicated the great potential of RA signaling as a therapeutic target for CRC. Fig.2. Modulation of RA signaling alters intestinal differentiation. (Wester, 2021)

References

Noman, M. A. A.; et al. Retinoic acid receptor antagonists for male contraception: current status. Biology of reproduction. 2020; 103(2): 390-399.
Wester, R.A.; et al. Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer. Iscience. 2021; 24(12): 103444.

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