The Impact Of SR Proteins And HnRNPA1 Splicing Factor Regulating The Alternative Splicing Of Human Glucocorticoid Receptor Exon 9

BackgroundGlucocorticoid (GC) insensitivity is a major clinical challenge in the treatment of many inflammatory diseases including asthma, but it's underlying molecular bases remain largely unknown. Increasing evidence showed that a relatively overabundance of hGRβ to hGRα may play an important role in the development of GC insensitivity. Human glucocorticoid receptor (hGR) pre-mRNA has a total of 9 exons, alternative splicing in exon 9 generates two highly homologous receptor: hGRα and hGRβ, both of them share the first 727 amino acid at their N termini coding by first eight exons, and differ only at their carboxyl-termini. hGRα has an additional 50 amino acids coding by exon 9a and hGRβ has an additional, nonhomologous 15 amino acids coding by exon9β. These differences render hGRβ unable to bind GCs, reduce its binding affinity for DNA recognition sites, abolish its ability to transactivate GC-sensitive genes. In transfected cells, hGRβ can inhibit the hGRα-mediated stimulation of gene expression via hGRα: hGRβ heterodimer formation. Therefore hGRβ is considered as dominant negative inhibitor of hGRα activity.The serine/arginine-rich (SR) proteins and hnRNPA1 are essential metazoan pre-mRNA splicing factors that play important roles in splice site selection, exon inclusion, and in the communication of splice sites, making them as the candidates for the factors postulated here to regulate alternative splicing. Given the intimate association of hGRβ with GC insensitivity, elucidation of the factors and cis-elements regulating alternative splicing of hGRβ are of key importance for delineation of the...