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J. Biol. Chem., Vol. 277, Issue 38, 35411-35421, September 20, 2002

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

Lucinda I. Chen^§¶, Karen M. Sommer^¶, and Karen Swisshelm

From the  Department of Pathology, University of Washington, Seattle, Washington 98195

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 gene between cells derived from normal human mammary glands and those derived from breast tumors. While the protein isoforms RAR2 and RAR4 consist of the longest open reading frames of the RAR2 and RAR4 mRNAs, respectively, we find that a fraction of scanning ribosomes bypass these upstream RAR2 and RAR4 protein start codons and initiate translation downstream. This downstream translation initiation site is identical in the RAR2 and RAR4 transcripts and generates a third RAR protein isoform, here termed RAR' (formerly human RAR4). RAR' lacks protein domains found in the N terminus of RAR2 and RAR4, including one of two zinc fingers required for DNA binding. However, RAR' retains the ability to heterodimerize with RXR and interact with transcription cofactors. In reporter gene assays, RAR' repressed retinoic acid-activated transcription of co-transfected RAR2, RAR4, and RAR. This repression required the presence of acidic amino acids within the AF2 domain. These findings demonstrate an antagonistic role for RAR' in signaling by retinoic acid.

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