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

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 TR beta 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, TR beta and PI3K on stanniocalcin 1 (STC1) expression in human cells. Design: We treated human skin fibroblasts with triiodothyronine (13) in the absence or presence of the PI3K inhibitor LY294002, a dominant Article negative PI3K subunit, Delta p85 alpha, and the protein synthesis inhibitor cycloheximide (CHX). The role of the TR beta 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 13 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 T(3) 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 TR beta and PI3K activation.