Thyroid Hormone Receptor α1 Regulates Expression of the Na+/H+ Exchanger (NHE1)*

In this paper we examine the role of thyroid hormone in regulating expression of the Na+/H+ exchanger. Thyroid hormone has been reported to regulate the activity of the Na+/H+ exchanger messenger RNA in some cell types. Treatment of cardiac myocytes with 3,5′,3′-triiodothyronine results in an increased expression of Na+/H+exchanger protein. Also, compared with euthyroid animals, hypothyroid rats express decreased amounts of the Na+/H+exchanger protein. To examine the mechanisms involved in regulating expression of the Na+/H+ exchanger, we have characterized the regulation of a distal element of the NHE1 promoter by the thyroid hormone receptor. We have previously shown that a −1085/−800 nucleotide (nt) region of the promoter is a modular element with a −841/−800 nt activating element. Using electrophoretic mobility shift assay, we show that this element interacts with thyroid hormone receptor TRα1, a nuclear hormone receptor. The addition of exogenous TRα increased transcriptional activity of the −841/−800 nt element of the Na+/H+ exchanger promoter. We show that TRα binds to a region on the −841/−800 nt element that is near, but not identical, to the previously identified chicken ovalbumin upstream promoter transcription factor-binding site. Our results are the first demonstration that thyroid hormone and the thyroid hormone receptor TRα1 regulate expression of the Na+/H+ exchanger.

[1]  G. Hunninghake,et al.  Mitochondrial K(ATP) channel openers activate the ERK kinase by an oxidant-dependent mechanism. , 2002, American journal of physiology. Cell physiology.

[2]  M. Karmazyn,et al.  Attenuation of compensatory right ventricular hypertrophy and heart failure following monocrotaline-induced pulmonary vascular injury by the Na+-H+ exchange inhibitor cariporide. , 2001, The Journal of pharmacology and experimental therapeutics.

[3]  L. Fliegel.  Regulation of myocardial Na+/H+ exchanger activity , 2001, Basic Research in Cardiology.

[4]  L. Fliegel,et al.  COUP-TFI and COUP-TFII regulate expression of the NHE through a nuclear hormone responsive element with enhancer activity. , 2001, European journal of biochemistry.

[5]  Lei Guo,et al.  COUP-TF1 Antagonizes Nkx2.5-mediated Activation of the Calreticulin Gene during Cardiac Development* , 2001, The Journal of Biological Chemistry.

[6]  J. Pouysségur,et al.  The Expanding Family of Eucaryotic Na+/H+Exchangers* , 2000, The Journal of Biological Chemistry.

[7]  C. Sylvén,et al.  Organ specific expression of thyroid hormone receptor mRNA and protein in different human tissues. , 1999, Biological & pharmaceutical bulletin.

[8]  L. Fliegel,et al.  Protein Kinase-mediated Regulation of the Na+/H+ Exchanger in the Rat Myocardium by Mitogen-activated Protein Kinase-dependent Pathways* , 1999, The Journal of Biological Chemistry.

[9]  L. Fliegel,et al.  Regulation of Na+/H+exchanger gene expression: mitogenic stimulation increases NHE1 promoter activity. , 1998, American journal of physiology. Cell physiology.

[10]  J. Bernal,et al.  Biological activities of thyroid hormone receptors. , 1997, European journal of endocrinology.

[11]  L. Fliegel,et al.  The Na+/H+ Antiporter Potentiates Growth and Retinoic Acid-induced Differentiation of P19 Embryonal Carcinoma Cells* , 1997, The Journal of Biological Chemistry.

[12]  B. Wolska,et al.  Changes in thyroid state affect pHi and Nai+ homeostasis in rat ventricular myocytes. , 1997, Journal of molecular and cellular cardiology.

[13]  J. Weiner,et al.  Regions Flanking Exon 1 Regulate Constitutive Expression of the Human Antithrombin Gene* , 1996, The Journal of Biological Chemistry.

[14]  D. Warnock,et al.  Renal Na+/H+ exchanger isoforms and their regulation by thyroid hormone. , 1996, The American journal of physiology.

[15]  N. Madias,et al.  Role of C/EBP proteins in hepatic and vascular smooth muscle transcription of human NHE1 gene. , 1995, The American journal of physiology.

[16]  L. Fliegel,et al.  The carboxyl-terminal region of the Na+/H+ exchanger interacts with mammalian heat shock protein. , 1995, Biochemistry.

[17]  L. Fliegel,et al.  Induction of expression of the sodium-hydrogen exchanger in rat myocardium. , 1995, Cardiovascular research.

[18]  L. Fliegel,et al.  Activation of the Na/H Exchanger Gene by the Transcription Factor AP-2 (*) , 1995, The Journal of Biological Chemistry.

[19]  M. Becker‐André,et al.  Thyroid hormone receptor functions as monomeric ligand-induced transcription factor on octameric half-sites. Consequences also for dimerization. , 1994, The Journal of biological chemistry.

[20]  D. Rosskopf,et al.  Enhanced Na(+)-H+ exchanger activity and NHE-1 mRNA levels in human lymphocytes during metabolic acidosis. , 1994, The American journal of physiology.

[21]  J. Capone,et al.  Identification of a peroxisome proliferator-responsive element upstream of the gene encoding rat peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[22]  P. Hallenbeck,et al.  Characterization of myelin basic protein thyroid hormone response element and its function in the context of native and heterologous promoter. , 1992, The Journal of biological chemistry.

[23]  S. Horie,et al.  Role of protein kinase C and transcription factor AP-1 in the acid-induced increase in Na/H antiporter activity. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[24]  C. Sardet,et al.  Na+/H+ antiporter gene expression increases during retinoic acid‐induced granulocytic differentiation of HL60 cells , 1992, Journal of cellular physiology.

[25]  S. Horie,et al.  Differential regulation of Na/H antiporter by acid in renal epithelial cells and fibroblasts. , 1991, The Journal of clinical investigation.

[26]  B. Desvergne,et al.  Identification of a thyroid hormone response element in the malic enzyme gene. , 1990, The Journal of biological chemistry.

[27]  C. Sardet,et al.  Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+ H+ , 1989, Cell.

[28]  S Grinstein,et al.  Na+/H+ exchange and growth factor-induced cytosolic pH changes. Role in cellular proliferation. , 1989, Biochimica et biophysica acta.

[29]  D. Rohrer,et al.  Thyroid hormone markedly increases the mRNA coding for sarcoplasmic reticulum Ca2+-ATPase in the rat heart. , 1988, The Journal of biological chemistry.

[30]  J. Kinsella,et al.  Thyroid hormones increase Na+-H+ exchange activity in renal brush border membranes. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[31]  R. Solaro,et al.  Thyroxine‐Induced Redistribution of Isoenzymes of Rabbit Ventricular Myosin , 1982, Circulation research.

[32]  J. Dussault,et al.  Free Thyroid Hormone Concentrations during Postnatal Development in the Rat , 1980, Pediatric Research.

[33]  E. Ballestar,et al.  Methyl-CpG-binding proteins. Targeting specific gene repression. , 2001, European journal of biochemistry.

[34]  O. Moe,et al.  Thyroid hormone stimulates the renal Na/H exchanger NHE3 by transcriptional activation. , 1999, American journal of physiology. Cell physiology.