Hyperactive Human Glucocorticoid Receptor Isoforms and their Implications for the Stress Response.
Glucocorticoids are indispensable therapeutic agents in diseases of inflammation, but their effectiveness in treating advanced septic shock has been inconsistent. Our understanding of the mechanisms causing this variability to steroid therapy remains limited. Previous studies in our laboratory have implicated human glucocorticoid receptor (hGR) polymorphisms as one of the likely reasons for this variability. We examined the effect of two single-nucleotide polymorphisms (SNPs) on the transactivation potential of the hGR in the absence and presence of exogenous steroids. An isoform containing a novel naturally occurring human SNP, T1463C, was found to have a hyperactive response with treatment of all three steroids examined while maintaining low activity in the absence of steroids, relative to reference hGR. In comparison, another hGR isoform with the A2297G SNP, previously identified in our laboratory, demonstrated hyperactive transactivational response in the absence of steroids; however, it had a significant increase in activity after treatment with only one of the glucocorticoids (hydrocortisone) tested. These results offer a possible explanation for the clinical variability seen among individuals in response to stress or shock.
Department of Surgery, University of California Davis Medical Center and Shriners Hospitals for Children Northern California, Sacramento, California.
Michael V
MV
Lasker
Stacey M
SM
Leventhal
Debora
D
Lim
Tajia L
TL
Green
Kelly
K
Tung
Kiho
K
Cho
David G
DG
Greenhalgh
D019943:Amino Acid Substitution; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D057809:HEK293 Cells; D064368:Healthy Volunteers; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects
D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; C411470:glucocorticoid receptor alpha; D003907:Dexamethasone; D006854:Hydrocortisone; D008775:Methylprednisolone