Retinoic acid receptor α1 variants, RARα1△B and RARα1△BC, define a new class of nuclear receptor isoforms

摘要

Retinoic acid (RA) binds and activates retinoid X receptor (RXR)/retinoic acid receptor (RAR) heterodimers, which regulate the transcription of genes that have retinoic acid response elements (RARE). The RAR isotypes (α, β and γ) are comprised of six regions designated A-F. Two isoforms of FARα, 1 and 2, have been identified in humans, which have different A regions generated by differential promoter usage and alternative splicing. We have isolated two new splice variants of RARα1 from human B lymphocytes. In one of these variants, exon 2 is juxtaposed to exon 5, resulting in an altered reading frame and a stop codon. This variant, designated RARα1△B, does not code for a functional receptor. In the second variant, exon 2 is juxtaposed to exon 6, maintaining the reading frame. This isoform, designated RARα1△BC, retains most of the functional domains of RARα1, but omits the transactivation domain AF-1 and the DNA-binding domain. Consequently, it does not bind nor transactivate RARE on its own. Nevertheless, RARα1△BC interacts with RXRα and, as an RXRα/RARα1△BC heterodimer, transactivates the DR5 RARE upon all-trans-RA binding. The use of RAR- and RXR-specific ligands shows that, whereas transactivation of the DR5 RARE through the RXRα/RARα1△BC heterodimer is mediated by RAR and RXR ligands. Whilst RARα1 has a broad tissue distribution, RARα1△BC has a more heterogeneous distribution, but with significant expression in myeloid cells. RARα1△BC is an infrequent example of a functional nuclear receptor which deletes the DNA-binding domain.