Downstream Codons in the retinoic acid receptor β-2 and β-4 mRNAs initiate translation of a protein isoform that disrupts retinoid-activated transcription

被引:19
作者
Chen, LI [1 ]
Sommer, KM [1 ]
Swisshelm, K [1 ]
机构
[1] Univ Washington, Dept Pathol, Seattle, WA 98195 USA
关键词
D O I
10.1074/jbc.M202717200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 RARbeta gene between cells derived from normal human mammary glands and those derived from breast tumors. While the protein isoforms RARbeta2 and RARbeta4 consist of the longest open reading frames of the RARbeta2 and RARbeta4 mRNAs, respectively, we find that a fraction of scanning ribosomes bypass these upstream RARbeta2 and RARbeta4 protein start codons and initiate translation downstream. This downstream translation initiation site is identical in the RARbeta2 and RARbeta4 transcripts and generates a third RARbeta protein isoform, here termed RARbeta' (formerly human RARbeta4). RARbeta' lacks protein domains found in the N terminus of RARbeta2 and RARbeta4, including one of two zinc fingers required for DNA binding. However, RARbeta' retains the ability to heterodimerize with RXRalpha and interact with transcription cofactors. In reporter gene assays, RARbeta' repressed retinoic acid-activated transcription of co-transfected RARbeta2, RARbeta4, and RARalpha. This repression required the presence of acidic amino acids within the AF2 domain. These findings demonstrate an antagonistic role for RARbeta' in signaling by retinoic acid.
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页码:35411 / 35421
页数:11
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