Downstream Codons in the Retinoic Acid Receptor [beta]-2 and [beta]-4 mRNAs Initiate Translation of a Protein Isoform That Disrupts Retinoid-activated Transcription

Retinoic acid receptors (RARs) are essential for the differentiation and maintenance of normal epithelium. In studies of RARs in breast cancer, there are striking differences in the expression of certain protein isoforms of the RAR[beta] gene between cells derived from normal human mammary glands and those derived from breast tumors. While the protein isoforms RAR[beta]2 and RAR[beta]4 consist of the longest open reading frames of the RAR[beta]2 and RAR[beta]4 mRNAs, respectively, we find that a fraction of scanning ribosomes bypass these upstream RAR[beta]2 and RAR[beta]4 protein start codons and initiate translation downstream. This downstream translation initiation site is identical in the RAR[beta]2 and RAR[beta]4 transcripts and generates a third RAR[beta] protein isoform, here termed RAR[beta]' (formerly human RAR[beta]4). RAR[beta]' lacks protein domains found in the N terminus of RAR[beta]2 and RAR[beta]4, including one of two zinc fingers required for DNA binding. However, RAR[beta]' retains the ability to heterodimerize with RXR[alpha] and interact with transcription cofactors. In reporter gene assays, RAR[beta]' repressed retinoic acid-activated transcription of co-transfected RAR[beta]2, RAR[beta]4, and RAR[alpha]. This repression required the presence of acidic amino acids within the AF2 domain. These findings demonstrate an antagonistic role for RAR[beta]' in signaling by retinoic acid.