This Article Full Text Full Text (PDF) All Versions of this Article: 19/12/2955    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moeller, L. C. Articles by Refetoff, S. Search for Related Content PubMed PubMed Citation Articles by Moeller, L. C. Articles by Refetoff, S.

Cytosolic Action of Thyroid Hormone Leads to Induction of Hypoxia-Inducible Factor-1 and Glycolytic Genes

Departments of Medicine (L.C.M., S.R.), Pediatrics (S.R.), and Human Genetics (A.M.D.) and Committees on Genetics and Molecular Medicine (S.R.), The University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Samuel Refetoff, M.D., The University of Chicago, MC3090, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}uchicago.edu.

Thyroid hormone (TH) effects are mediated through T₃, which regulates gene expression by binding to the nuclear TH receptors, TR and TRß. Using microarrays and real-time PCR we found mRNAs of the following genes increased in response to T₃ in a TRß-specific manner: the transcription factor hypoxia-inducible factor (HIF)-1, its target genes glucose transporter (GLUT)1 and platelet-type phosphofructokinase (PFKP), and the monocarboxylate transporter (MCT)4. The products of these genes have important roles in cellular glucose metabolism. HIF-1 expression and activity can be regulated through phosphatidylinositol-OH-3-kinase (PI3K) and MAPK signaling; thus the possibility of alternative, nonnuclear pathways of TH action was raised. We examined the involvement of these pathways in mediating TH effects by treating human skin fibroblasts with 2 nM T₃ in the absence or presence of either the PI3K inhibitor LY294002 or the MAPK inhibitor PD98059. T₃ induced HIF-1 mRNA by 2.7-fold (±0.4; P < 0.013). This increase was completely abrogated by LY294002 (1.1 ± 0.1; nonsignificant = 0.57), but preserved in the presence of PD98059 (2.2 ± 0.2; P < 0.009). Western blotting confirmed these results at the protein level, indicating dependency on the PI3K pathway. The same pattern of response was observed for GLUT1, PFKP, and MCT4 expression. To examine whether HIF-1 is directly induced, we used the translation inhibitor cycloheximide (CHX). T₃ induction of HIF-1 mRNA was not affected by CHX, whereas T₃ effect on GLUT1, PFKP, and MCT4 mRNA was completely abrogated by CHX. These results demonstrate that cytosolic activation of the PI3K signaling pathway has a role in TH-mediated direct (HIF-1) and indirect (GLUT1, PFKP, MCT4) gene expression, and possibly provides a link between TH and cellular glucose metabolism in human fibroblasts.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Ligands:   Thyroid hormone

This article has been cited by other articles:

				A. Wulf, M. G Wetzel, M. Kebenko, M. Kroger, A. Harneit, J. Merz, and J. M Weitzel The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription J. Mol. Endocrinol., July 1, 2008; 41(1): 25 - 34. [Abstract] [Full Text] [PDF]

				T. Otto and J. Fandrey Thyroid Hormone Induces Hypoxia-Inducible Factor 1{alpha} Gene Expression through Thyroid Hormone Receptor {beta}/Retinoid X Receptor {alpha}-Dependent Activation of Hepatic Leukemia Factor Endocrinology, May 1, 2008; 149(5): 2241 - 2250. [Abstract] [Full Text] [PDF]

				S. M. Gallagher, J. J. Castorino, D. Wang, and N. J. Philp Monocarboxylate Transporter 4 Regulates Maturation and Trafficking of CD147 to the Plasma Membrane in the Metastatic Breast Cancer Cell Line MDA-MB-231 Cancer Res., May 1, 2007; 67(9): 4182 - 4189. [Abstract] [Full Text] [PDF]

				E. Martin-Rendon, S. J.M. Hale, D. Ryan, D. Baban, S. P. Forde, M. Roubelakis, D. Sweeney, M. Moukayed, A. L. Harris, K. Davies, et al. Transcriptional Profiling of Human Cord Blood CD133+ and Cultured Bone Marrow Mesenchymal Stem Cells in Response to Hypoxia Stem Cells, April 1, 2007; 25(4): 1003 - 1012. [Abstract] [Full Text] [PDF]

				F. Flamant, K. Gauthier, and J. Samarut Thyroid Hormones Signaling Is Getting More Complex: STORMs Are Coming Mol. Endocrinol., February 1, 2007; 21(2): 321 - 333. [Abstract] [Full Text] [PDF]

				M. S. Ullah, A. J. Davies, and A. P. Halestrap The Plasma Membrane Lactate Transporter MCT4, but Not MCT1, Is Up-regulated by Hypoxia through a HIF-1{alpha}-dependent Mechanism J. Biol. Chem., April 7, 2006; 281(14): 9030 - 9037. [Abstract] [Full Text] [PDF]

				P. M. Yen Thyroid hormones and 3,5-diiodothyropropionic Acid: new keys for new locks. Endocrinology, April 1, 2006; 147(4): 1598 - 1601. [Full Text] [PDF]