Download PDF
Exp Clin Endocrinol Diabetes 2011; 119(2): 81-85
DOI: 10.1055/s-0030-1262860
Article

© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

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

L. C. Moeller1 , N. E. Haselhorst1 , A. M Dumitrescu2 , X. Cao4 , H. Seo4 , S. Refetoff2 , 3 , K. Mann1 , O. E. Janssen1 , 5
  • 1Department of Endocrinology and Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany
  • 2Department of Medicine, The University of Chicago, Chicago, Illinois, USA
  • 3Department of Pediatrics and Committees on Genetics and Molecular Medicine, The University of Chicago, Chicago, Illinois, USA
  • 4Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
  • 5Present Address: Endokrinologikum, Hamburg 22767, Germany
Further Information

Publication History

received 24.03.2010 first decision 28.06.2010

accepted 20.07.2010

Publication Date:
08 September 2010 (online)

Also available at
    Permissions and Reprints

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

References

  • 1 Cao X, Kambe F, Moeller LC. et al . Thyroid hormone induces rapid activation of Akt/protein kinase B-mammalian target of rapamycin-p70S6K cascade through phosphatidylinositol 3-kinase in human fibroblasts.  Mol Endocrinol. 2005;  19 102-112
    Google Scholar
  • 2 Chakraborty A, Brooks HL, Zhang P. et al . Stanniocalcin-1 regulates endothelial gene expression and modulates trans-endothelial migration of leukocytes.  Am J Physiol Renal Physiol. 2007;  292 895-904
    Google Scholar
  • 3 Chang AC, Janosi J, Hulsbeek M. et al . A novel human cDNA highly homologous to the fish hormone stanniocalcin.  Mol Cell Endocrinol. 1995;  112 241-247
    Google Scholar
  • 4 Chang AC, Jellinek DA, Reddel RR. Mammalian stanniocalcins and cancer.  Endocr Relat Cancer. 2003;  10 359-373
    Google Scholar
  • 5 Cheng SY, Leonard JL, Davis PJ. Molecular Aspects of Thyroid Hormone Actions.  Endocr Rev. 2010;  31 139-170
    Google Scholar
  • 6 Davis FB, Mousa SA, O’Connor L. et al . Proangiogenic action of thyroid hormone is fibroblast growth factor-dependent and is initiated at the cell surface.  Circ Res. 2004;  94 1500-1506
    Google Scholar
  • 7 Davis FB, Tang HY, Shih A. et al . Acting via a cell surface receptor, thyroid hormone is a growth factor for glioma cells.  Cancer Res. 2006;  66 7270-7275
    Google Scholar
  • 8 Filvaroff EH, Guillet S, Zlot C. et al . Stanniocalcin 1 alters muscle and bone structure and function in transgenic mice.  Endocrinology. 2002;  143 3681-3690
    Google Scholar
  • 9 Furuya F, Hanover JA, Cheng SY. Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor.  Proc Natl Acad Sci USA. 2006;  103 1780-1785
    Google Scholar
  • 10 Lal A, Peters H, St Croix B. et al . Transcriptional response to hypoxia in human tumors.  J Natl Cancer Inst. 2001;  93 1337-1343
    Google Scholar
  • 11 Law AY, Ching LY, Lai KP. et al . Identification and characterization of the hypoxia-responsive element in human stanniocalcin-1 gene.  Mol Cell Endocrinol. 2010;  314 118-127
    Google Scholar
  • 12 Lei J, Mariash CN, Ingbar DH. 3,3′,5-Triiodo-L-thyronine up-regulation of Na, K-ATPase activity and cell surface expression in alveolar epithelial cells is Src kinase- and phosphoinositide 3-kinase-dependent.  J Biol Chem. 2004;  279 47589-47600
    Google Scholar
  • 13 Livak KJS, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.  Methods. 2001;  25 402-408
    Google Scholar
  • 14 Madsen KL, Tavernini MM, Yachimec C. et al . Stanniocalcin: a novel protein regulating calcium and phosphate transport across mammalian intestine.  Am J Physiol. 1998;  274 G96-G102
    Google Scholar
  • 15 McCudden CR, James KA, Hasilo C. et al . Characterization of mammalian stanniocalcin receptors. Mitochondrial targeting of ligand and receptor for regulation of cellular metabolism.  J Biol Chem. 2002;  277 45249-45258
    Google Scholar
  • 16 Moeller LC, Cao X, Dumitrescu AM. et al . Thyroid hormone mediated changes in gene expression can be initiated by cytosolic action of the thyroid hormone receptor beta through the phosphatidylinositol 3-kinase pathway.  Nucl Recept Signal. 2006;  4 e020
    Google Scholar
  • 17 Moeller LC, Dumitrescu AM, Refetoff S. Cytosolic action of thyroid hormone leads to induction of hypoxia-inducible factor-1alpha and glycolytic genes.  Mol Endocrinol. 2005a;  19 2955-2963
    Google Scholar
  • 18 Moeller LC, Dumitrescu AM, Walker RL. et al . Thyroid hormone responsive genes in cultured human fibroblasts.  J Clin Endocrinol Metab.. 2005b;  90 936-943
    Google Scholar
  • 19 Murata Y, Ceccarelli P, Refetoff S. et al . Thyroid hormone inhibits fibronectin synthesis by cultured human skin fibroblasts.  J Clin Endocrinol Metab. 1987;  64 334-339
    Google Scholar
  • 20 Samuels HH, Stanley F, Casanova J. Depletion of L-3,5,3–triiodothyronine and L-thyroxine in euthyroid calf serum for use in cell culture studies of the action of thyroid hormone.  Endocrinology. 1979;  105 80-85
    Google Scholar
  • 21 Sheikh-Hamad D, Bick R, Wu GY. et al . Stanniocalcin-1 is a naturally occurring L-channel inhibitor in cardiomyocytes: relevance to human heart failure.  Am J Physiol Heart Circ Physiol. 2003;  285 H442-H448
    Google Scholar
  • 22 Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism.  J Biol Chem. 2006;  281 9030-9037
    Google Scholar
  • 23 Wagner GFD, Dimattia GE. The stanniocalcin family of proteins.  J Exp Zoolog A Comp Exp Biol. 2006;  305 769-780
    Google Scholar
  • 24 Yen PM. Physiological and molecular basis of thyroid hormone action.  Physiol Rev. 2001;  81 1097-1142
    Google Scholar
  • 25 Yeung HY, Lai KP, Chan HY. et al . Hypoxia-inducible factor-1-mediated activation of stanniocalcin-1 in human cancer cells.  Endocrinology. 2005;  146 4951-4960
    Google Scholar

Correspondence

L. C. Moeller

Department of Endocrinology

University of Duisburg-Essen

Hufelandstraße 55

45122 Essen

Germany

Phone: +49/201/723 2821

Fax: +49/201/723 5187

Email: lars.moeller@uni-due.de

      >