Possible link between the synthesis of GR alpha isoforms and eIF2 alpha phosphorylation state

Glucocorticoid hormones regulate numerous physiological processes and are widely used in the treatment of inflammation, autoimmune disease and cancer. Glucocorticoid receptor (GR) – a transcription factor, derived from a single gene, is responsible for the diverse actions of glucocorticoids. It was shown that GR gene gives rise a variety of mRNA species that produces several protein isoforms, among them GRα is the most abundant. In addition, GRα N-end-truncated protein isoforms (A, B, C, D) are generated by translational mechanisms. As it was found that the ratio between the translational isoforms amounts varied in different tissues and cell lines and distinct isoforms could control transcription of different sets of genes, molecular mechanisms underlining the synthesis of translational GRα isoforms are of great interest.It was considered that GRα isoform A is translated by a conventional linear scanning, isoform B is translated by leaky scanning, isoform C is translated by leaky scanning and ribosomal shunt whereas translation of isoform D occurs through ribosomal shunt only. Since the sequence organization of GRα mRNA strongly resembles the cases of ATF4 or ATF5, the well-known examples of reinitiation-dependent synthesis of functional isoforms, we hypothesize that translation of isoform C could be controlled by reinitiation mechanism also. If this assumption is correct, the ratio between GRα N-end isoforms could depend on the eIF2α phosphorylation state that could provide an additional connection between the GR and cellular stresses. We believe that this hypothesis could be of interest to plan more robust experiments or for better interpretation of available data.