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Nucleic Acids Research, 2001, Vol. 29, No. 24 4901-4908
© 2001 Oxford University Press

Retinoic acid receptor {alpha}1 variants, RAR{alpha}1{Delta}B and RAR{alpha}1{Delta}BC, define a new class of nuclear receptor isoforms

Antonio Parrado1,2,3,*, Gilles Despouy1, Radhia Kraïba1, Carole Le Pogam1, Stéphane Dupas1,2, Maryline Choquette1, Macarena Robledo1,2, Jérôme Larghero1, Hung Bui4, Isabelle Le Gall4, Cécile Rochette-Egly5, Christine Chomienne1 and Rose Ann Padua1,2

1Laboratoire de Biologie Cellulaire Hématopoïétique, INSERM U00-03, Université D. Diderot–Paris VII, Institut d’Hématologie, Hôpital Saint-Louis, Paris, France, 2Department of Haematology, University of Wales College of Medicine, Cardiff, UK, 3Sección de Inmunología, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain, 4Fondation Jean Dausset–CEPH, Hôpital Saint-Louis, Paris, France and 5Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

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}, ß 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{alpha}1 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{alpha}1{Delta}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 RAR{alpha}1{Delta}BC, retains most of the functional domains of RAR{alpha}1, 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{alpha}1{Delta}BC interacts with RXR{alpha} and, as an RXR{alpha}/RAR{alpha}1{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{alpha}1 heterodimer is mediated only by RAR ligands, transactivation through the RXR{alpha}/RAR{alpha}1{Delta}BC heterodimer is mediated by RAR and RXR ligands. Whilst RAR{alpha}1 has a broad tissue distribution, RAR{alpha}1{Delta}BC has a more heterogeneous distribution, but with significant expression in myeloid cells. RAR{alpha}1{Delta}BC is an infrequent example of a functional nuclear receptor which deletes the DNA-binding domain.

* To whom correspondence should be addressed at: Sección de Inmunología, Hospital Universitario Virgen de la Arrixaca, El Palmar 30120, Murcia, Spain. Tel: +34 968 36 95 99; Fax: +34 968 36 96 78; Email: aparrado{at}ono.com


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