Article

Increased Expression of the Glucocorticoid Receptor-A Translational Isoform as a Result of the ER22/23EK Polymorphism

Department of Internal Medicine, Room Ee 593, Erasmus MC, University Medical Center Rotterdam, Molewaterplein 40, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Molecular Endocrinology (Impact Factor: 4.02). 08/2005; 19(7):1687-96. DOI: 10.1210/me.2004-0467
Source: PubMed

ABSTRACT

One of the most intriguing polymorphisms in the GR [glucocorticoid (GC) receptor] gene is in codons 22 and 23 [GAGAGG(GluArg) --> GAAAAG (GluLys)]. This polymorphism is associated with a reduced GC sensitivity, a better metabolic and cardiovascular health profile, and an increased survival rate. Recently, Yudt and Cidlowski reported that two different methionine codons in the GR mRNA may be used as initiation codon: AUG-1 and AUG-27, resulting in two isoforms, the GR-A and the GR-B proteins, respectively. They also showed that the GR-B protein had a stronger transactivating effect in transient transfection experiments. In this study, we elucidated the molecular basis for the reduced GC sensitivity by investigating the influence of the ER22/23EK polymorphism on synthesis of GR-A and GR-B by expressing them independently from constructs with and without the polymorphic site. Binding studies with [(3)H]-dexamethasone and transactivation studies showed that, when the ER22/23EK polymorphism is present, approximately 15% more GR-A protein was expressed, whereas total GR levels (GR-A + GR-B) were not affected. These results show that the transcriptional activity in GR(ER22/23EK) carriers is decreased because more of the less transcriptionally active GR-A isoform is formed. This is probably caused by altered secondary mRNA structure.

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Available from: Elisabeth FC van Rossum
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    • "In a study of patients with depression, carrier of the ER22/23EK polymorphism had higher rates of recurrent major depression episodes and responded faster to treatment with antidepressants [63,64]. A possible explanation could be the higher concentration of the less active GR variant which could lead to GC resistance [65]. An association between the BclI polymorphism and major depression has been found in several studies. "
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    • "This polymorphism has been associated with relative GC resistance (Russcher et al., 2005a; van Rossum et al., 2002). In vitro analyses have associated this SNP with reduced transactivating capacity of the GR due to a higher expression of the GR-A isoform (Russcher et al., 2005b). The N363S polymorphism results from one nucleotide substitution in codon 363 of exon 2, and the subsequent alteration from asparagine (N) to serine (S) (Koper et al., 1997 ). "
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    • "Furthermore, recent findings from in vitro and in vivo studies have demonstrated the important new role of old molecules, such as the serumand glucocorticoid-inducible kinase 1 (SGK1) [16,17] and FK506 -binding protein 51 (FKBP5) [18,19], in tissue sensitivity to glucocorticoids and associated pathologic conditions. In addition to protein-protein interactions, tissue responsiveness to glucocorticoids has become more complicated since the identification and functional characterization of hGR polymorphisms2021222324. Interestingly, MR polymorphisms may also play some roles in tissue glucocorticoid sensitivity [25]. "
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