The Alternative Noncoding Exons 1 of Aromatase (Cyp19) Gene Modulate Gene Expression in a Posttranscriptional Manner

• Published in: Endocrinology (Philadelphia) 2009-07, Vol.150 (7), p.3301-3307
• Main Authors: Wang, Hanzhou, Li, Rong, Hu, Yanfen
• Format: Article
• Language: English
• Subjects: Abundance; Adipose tissue; Amino acid sequence; Aromatase; Aromatase - genetics; Biological and medical sciences; Biosynthesis; Endocrine therapy; Estrogen receptors; Estrogens; Exons; Exons - physiology; Expression vectors; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Enzymologic; Gene sequencing; Humans; mRNA stability; Nucleotide sequence; Post-menopause; Post-transcription; Promoter Regions, Genetic; Promoters; Proteins; Regulatory mechanisms (biology); Regulatory sequences; Relative abundance; RNA Processing, Post-Transcriptional - physiology; RNA, Messenger - metabolism; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2008-1812

Aromatase (Cyp19) is a key enzyme in estrogen biosynthesis and an important target in endocrine therapy for estrogen receptor (ER)-positive postmenopausal breast cancer. Aromatase transcription is driven by multiple tissue-specific promoters, which result in the production of various mRNA transcripts that contain an alternative noncoding exon 1 followed by a common protein-coding region. Transcriptional activity of these promoters is the only known determinant for aromatase protein abundance in a given tissue or cellular context. To determine whether aromatase expression could be influenced by additional regulatory mechanisms, we used a common heterologous promoter to drive the expression of multiple aromatase cDNA sequences that differ only by the alternative exon 1 sequence. These expression vectors gave rise to vastly different levels of aromatase mRNA and protein in multiple cell lines examined. Furthermore, the relative abundance of several mRNA variants did not correlate with that of the corresponding protein product. The variation in mRNA and protein levels is most likely due to a negative effect of certain alternative exons 1 on RNA stability and protein translation. Deletional analyses indicate that the 5′ regions of the adipose tissue-specific exons I.3 and I.4 contain the cis-acting elements responsible for modulation of aromatase levels. Thus, our work uncovers an important role of the alternative exons 1 in posttranscriptional regulation of aromatase gene expression. Aromatase expression is controlled by a post-transcriptional mechanism.