Endocrine Abstracts

The 5′ UTR of the glucocorticoid receptor plays a key role in determining tissue specific expression, and protein isoforms. Analysis of the 5′ UTR of the hGR has revealed 11 splice variants of the hGR exon 1, based on 7 exon 1 s, 4 of which (1-D to 1-F and 1-H) were previously unknown. All of the exon 1 variants have unique splice donor sites and share a common exon 2 splice acceptor site. Due to an upstream in-frame TGA stop codon the predicted translation from all splice variants is identical. The four new exon 1 s show remarkable similarity with their rat homologues. Exon 1-D starts and finishes 17- and 36 bp upstream of the corresponding ends of the rat exon 1₄. Exon 1-E is only 6 bp longer than its homologue 1₅. Exon 1-F contains two short inserts of 11- and 6 bp when compared to the rat 1₇. 1-H is 18 bp longer than the corresponding rat 1₁₁. In addition to these new exons, we found that the human exon 1-C occurs as 3 distinct splice variants, covering the region homologous to the rat exons 1₉ and 1₁₀. All of the alternative hGR exons 1 s presented here were found to be transcribed in human tissue. The human hippocampus expresses mRNA of all the exon 1 variants, whilst the expression of the other exon 1 s seems to be tissue-specific. While exon 1-D is only in the hippocampus, exons 1-E and 1-F are also detected in the immune system, and exon 1-H additionally in the liver, lung and smooth muscle. The 5′ region of the hGR is more complex than previously thought, and we suggest that each of these untranslated first exons have a distinct proximal promoter region, providing additional depth to the mechanisms available for tissue specific expression of the hGR isoforms.