Stanniocalcin 1 induction by thyroid hormone depends on thyroid hormone receptor β and phosphatidylinositol 3-kinase activation

• Published in: Experimental and clinical endocrinology & diabetes Vol. 119; no. 2; p. 81
• Main Authors: Moeller, L C, Haselhorst, N E, Dumitrescu, A M, Cao, X, Seo, H, Refetoff, S, Mann, K, Janssen, O E
• Format: Journal Article
• Language: English
• Published: Germany 01.02.2011
• Subjects: Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Fibroblasts - physiology; Gene Expression Regulation - drug effects; Glycoproteins - genetics; Glycoproteins - metabolism; Humans; Mutant Proteins - metabolism; Mutant Proteins - physiology; Phosphatidylinositol 3-Kinase - metabolism; Protein Biosynthesis - drug effects; Protein Biosynthesis - genetics; Thyroid Hormone Receptors beta - agonists; Thyroid Hormone Receptors beta - genetics; Thyroid Hormone Receptors beta - metabolism; Thyroid Hormone Receptors beta - physiology; Thyroid Hormone Resistance Syndrome - genetics; Thyroid Hormone Resistance Syndrome - metabolism; Thyroid Hormone Resistance Syndrome - pathology; Transcriptional Activation - drug effects; Triiodothyronine - pharmacology
• DOI: 10.1055/s-0030-1262860

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