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

Abstract:

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 RARα, 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 RARα1ΔB, 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 RARα1ΔBC, 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, RARα1ΔBC interacts with RXRα and, as an RXRα/RARα1ΔBC 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 heterodimer is mediated only by RAR ligands, transactivation through the RXRα/RARα1ΔBC heterodimer is mediated by RAR and RXR ligands. Whilst RARα1 has a broad tissue distribution, RARα1ΔBC has a more heterogeneous distribution, but with significant expression in myeloid cells. RARα1ΔBC is an infrequent example of a functional nuclear receptor which deletes the DNA-binding domain.