A New Transcript Splice Variant of the Human Glucocorticoid Receptor: Identification and Tissue Distribution of hGR△313-338, an Alternative Exon 2 Transactivation Domain Isoform

摘要

All human glucocorticoid receptor (hGR) isoforms are en coded by the NR3C1 gene consisting of seven core exons (exons 2-8) common to all protein isoforms. The gene has two major exon 8-9 splice variants and a 5'-UTR consisting of 11 alternative splice variants. The N terminal region of the hGR includes a tau 1 transactivation domain that interacts with proteins in the basal transcriptional apparatus, including the TATA box-binding protein. Here, we report the existence and the tis sue distribution of a novel splice variant, hGR △313-338, with a 26 residue (78 bp) deletion in this N-terminal region encoded by exon 2, between amino acids 313 and 338. The hGR△313-338 observed at the mRNA level represents a transcript variant encoding a smaller protein isoform de tected by WB with a predicted deletion between the tau 1 domain and the DNA-binding domain (DBD) encoded by exons 3 and 4. Previous studies in transgenic mice showed that the removal of the entire exon 2 covering both the tau 1 transactivation domain and our deleted region produced a functional receptor albeit with an altered glucocorticoid-induced gene transcription pattern. Interestingly, the deleted residues show a number of potential phosphorylation sites including serine 317, known to be phos phorylated. It is thought that phosphorylation plays an important role in transactivation action of hGR. Thus, we hypothesize that hGR△313-338 represents a hGR isoform with an altered glucocorticoid-induced transactivation profile.