Stanniocalcin 1 induction by thyroid hormone depends on thyroid hormone receptor β and phosphatidylinositol 3-kinase activation.
BACKGROUND
Thyroid hormone (TH) mediated changes in gene expression were thought to be primarily initiated by the nuclear TH receptor (TR) binding to a thyroid hormone response element in the promoter of target genes. A recently described extranuclear mechanism of TH action consists of the association of TH-liganded TRβ with phosphatidylinositol 3-kinase (PI3K) in the cytosol and subsequent activation of the PI3K pathway.


OBJECTIVE
The aim of this study was to examine the effect of TH, TRβ and PI3K on stanniocalcin 1 (STC1) expression in human cells.


METHODS
We treated human skin fibroblasts with triiodothyronine (T3) in the absence or presence of the PI3K inhibitor LY294002, a dominant negative PI3K subunit, Δp85α, and the protein synthesis inhibitor cycloheximide (CHX). The role of the TRβ was studied in cells from patients with resistance to thyroid hormone (RTH). STC-1 mRNA expression was measured by real-time PCR.


RESULTS
We found an induction of STC1 by T3 in normal cells, but less in cells from subjects with RTH (2.7 ± 0.2 vs. 1.6 ± 0.04, P < 0.01). The effect of T3 was completely abrogated by blocking PI3K with LY294002 (3.9 ± 0.5 vs. 0.85 ± 0.5; P < 0.05) and greatly reduced after transfection of a dominant negative PI3K subunit, demonstrating dependency on the PI3K pathway.


CONCLUSIONS
These results establish STC1 as a TH target gene in humans. Furthermore, we show that STC1 induction by TH depends on both TRβ and PI3K activation.
Moeller
L C
LC
Department of Endocrinology and Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany. lars.moeller@uni-due.de
Haselhorst
N E
NE
Dumitrescu
A M
AM
Cao
X
X
Seo
H
H
Refetoff
S
S
Mann
K
K
Janssen
O E
OE
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism / Q000502:physiology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation / Q000187:drug effects; D014284:Triiodothyronine / Q000494:pharmacology*
D006023:Glycoproteins; D050505:Mutant Proteins; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; C051795:teleocalcin; D058539:Phosphatidylinositol 3-Kinase
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