PMID- 25394249

OWN - NLM
STAT- MEDLINE
DCOM- 20160422
LR - 20150620
IS - 1540-0514 (Electronic)
IS - 1073-2322 (Linking)
VI - 43
IP - 3
DP - 2015 Mar
TI - Hyperactive Human Glucocorticoid Receptor Isoforms and their Implications for
the
Stress Response.
PG - 228-32
LID - 10.1097/SHK.0000000000000289 [doi]
AB - 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.
FAU - Lasker, Michael V
AU - Lasker MV
AD - Department of Surgery, University of California Davis Medical Center and
Shriners
Hospitals for Children Northern California, Sacramento, California.
FAU - Leventhal, Stacey M
AU - Leventhal SM
FAU - Lim, Debora
AU - Lim D
FAU - Green, Tajia L
AU - Green TL
FAU - Tung, Kelly
AU - Tung K
FAU - Cho, Kiho
AU - Cho K
FAU - Greenhalgh, David G
AU - Greenhalgh DG
LA - eng
PT - Journal Article
PT - Research Support, Non-U.S. Gov't
PL - United States
TA - Shock
JT - Shock (Augusta, Ga.)
JID - 9421564
RN - 0 (Protein Isoforms)
RN - 0 (Receptors, Glucocorticoid)
RN - 0 (Recombinant Proteins)
RN - 0 (glucocorticoid receptor alpha)
RN - 7S5I7G3JQL (Dexamethasone)
RN - WI4X0X7BPJ (Hydrocortisone)
RN - X4W7ZR7023 (Methylprednisolone)
SB - IM
MH - Amino Acid Substitution
MH - Dexamethasone/pharmacology
MH - Female
MH - HEK293 Cells
MH - Healthy Volunteers
MH - Humans
MH - Hydrocortisone/pharmacology
MH - Male
MH - Methylprednisolone/pharmacology
MH - Mutation, Missense
MH - *Polymorphism, Single Nucleotide
MH - Protein Isoforms/chemistry/genetics/metabolism
MH - Receptors, Glucocorticoid/chemistry/*genetics/*metabolism
MH - Recombinant Proteins/chemistry/genetics/metabolism
MH - Stress, Physiological/drug effects/*genetics/*physiology
MH - Transcriptional Activation/drug effects
EDAT- 2014/11/14 06:00
MHDA- 2016/04/23 06:00
CRDT- 2014/11/14 06:00
PHST- 2014/11/14 06:00 [entrez]
PHST- 2014/11/14 06:00 [pubmed]
PHST- 2016/04/23 06:00 [medline]
AID - 10.1097/SHK.0000000000000289 [doi]
PST - ppublish
SO - Shock. 2015 Mar;43(3):228-32. doi: 10.1097/SHK.0000000000000289.