Retinoic acid receptor α1 variants, RARα1ΔB RARα1ΔBC, define a new class of nuclear receptor isoforms

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 (alpha, beta and gamma) are comprised of six regions designated A-F. Two isoforms of RAR alpha, 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 RAR alpha1 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 RAR alpha1 DeltaB, 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 RAR alpha1 Delta BC, retains most of the functional domains of RAR alpha1, but omits the transactivation domain AF-1 and the DNA-binding domain. Consequently, it does not bind nor transactivate RARE on its own. Nevertheless, RAR alpha1 Delta BC interacts with RXR alpha and, as an RXR alpha /RAR alpha1 Delta 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 RXR alpha /RAR alpha1 heterodimer is mediated only by RAR ligands, transactivation through the RXR alpha /RAR alpha1 Delta BC heterodimer is mediated by RAR and RXR ligands. Whilst RAR alpha1 has a broad tissue distribution, RAR alpha1 Delta BC has a more heterogeneous distribution, but with significant expression in myeloid cells. RAR alpha1 Delta BC is an infrequent example of a functional nuclear receptor which deletes the DNA-binding domain.