NUCLEAR RECEPTORS

Retinoic acid regulates transcription by binding and activating the ligand-dependent transcription factors known as retinoic acid receptors (RARs), which form heterodimers with retinoid X receptors (RXRs). RARs and RXRs are members of the nuclear receptor superfamily of transcription factors. The nuclear receptor superfamily comprises more than 150 members. Other members of this family include the steroid receptors:

• Steroid hormone receptors (e.g. glucocorticoid receptor (GR), estrogen receptor (ER), androgen receptor (AR)
• RXR heterodimers (e.g. thyroid hormone receptor (TR), liver X receptor (LXR), peroxisome proliferator-activated receptors (PPARs), and vitamin D receptor (VDR).

Click START ANIMATION

The nuclear receptor for retinoic acid (RAR) is activated by its ligand all-trans retinoic acid (at-RA) whereas the receptor retinoid X receptor (RXR) is activated by 9-cis retinoic acid (9c-RA).

Nuclear receptor activation

The nuclear receptors of Type 2 are bound to their DNA response element (RE) as a heterodimer with retinoid X receptor (RXR).

1 In the absence of ligand, the nuclear receptors are bound to corepressor complexes that inhibit transcription.

2 The ligand binding leads to a conformational change of the receptors, which leads to dissociation of corepressors from the receptors.

3 The ligand binding also leads to recruitment of coactivator complexes and other protein complexes (general transcription factors) that are required for transcription of the target gene by RNA polymerase II (RNA Pol II).

Sub-families in the nuclear receptor superfamily

RXR heterodimers

There are six different retinoic acid receptors . The receptors bind DNA as heterodimers. RAR binds all-trans retinoic acid and 9-cis retinoic acid. It is not known whether 9-cis-retinoic acid is found in vivo; if so, it is only present in very small amounts that are impossible to detect.

(For references see Mangelsdorf et al. 1995; Mangelsdorf & Evans 1995 and ref. therein).

VITAMIN A TARGET GENES:

Many of the vitamin A target genes are involved in vitamin A metabolism, e.g. the enzyme LRAT. Other target genes are transcription factors involved in development and differentiation.

From an article in Journal of Lipid Research, 2000:

Retinoic acid stimulates esterification of retinol for storage by inducing expression of LRAT