Stanniocalcin 1 Induction by Thyroid Hormone Depends on Thyroid Hormone Receptor β and Phosphatidylinositol 3-kinase Activation

Abstract

Context: 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.

Design: 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.

Conclusion: 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.

Key words

nongenomic action - hypoxia inducible factor 1 - HIF-1

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