Taurine 7 pp 523-532 | Cite as

Involvement of Transcriptional Factor TonEBP in the Regulation of the Taurine Transporter in the Cardiomyocyte

  • Takashi Ito
  • Yasushi Fujio
  • Stephen W. Schaffer
  • Junichi Azuma
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 643)


Taurine is found in high concentrations in heart where it exerts several actions that could potentially benefit the diseased heart. The taurine transporter (TauT) is crucial for the maintenance of high taurine levels in the heart. Although cardiac taurine content is altered in various pathological conditions, little is known about the regulatory mechanisms governing TauT expression in cardiac myocytes. In the present study, we found that treatment with the antineoplastic drug doxorubicin (DOX), which is also known as a cardiotoxic agent, decreases the expression of the TauT gene in cultured cardiomyocytes isolated from the neonatal rat heart. Based on data obtained using a luciferase assay, DOX significantly reduced transcriptional activity driven by the TauT promoter, while deletion or mutation of a tonicity-response element (TonE) in this promoter eliminated the change of promoter activity. The protein level of the TonE-binding protein (TonEBP) was reduced by DOX treatment. In addition, the reduction in TonEBP protein content was suppressed by proteasome inhibitors. In conclusion, the DOX-enhanced degradation of TonEBP resulting in reduced TauT expression in the cardiomyocyte.


Cardiac Myocytes Aldose Reductase Taurine Transporter Taurine Content TauT Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Arai M, Tomaru K, Takizawa T, Sekiguchi K, Yokoyama T, Suzuki T, Nagai R (1998) Sarcoplasmic reticulum genes are selectively down-regulated in cardiomyopathy produced by doxorubicin in rabbits. J Mol Cell Cardiol 30:243–254PubMedCrossRefGoogle Scholar
  2. Chapman RA, Suleiman MS, Earm YE (1993) Taurine and the heart. Cardiovasc Res 27:358–363PubMedCrossRefGoogle Scholar
  3. Chesney RW (1985) Taurine: its biological role and clinical implications. Adv Pediatr 32:1–42PubMedGoogle Scholar
  4. Hamaguchi T, Azuma J, Harada H, Takahashi K, Kishimoto S, Schaffer SW (1989) Protective effect of taurine against doxorubicin-induced cardiotoxicity in perfused chick hearts. Pharmacol Res 21:729–734PubMedCrossRefGoogle Scholar
  5. Han X, Chesney RW (2003) Regulation of taurine transporter gene (TauT) by WT1. FEBS Lett 540:71–76PubMedCrossRefGoogle Scholar
  6. Han X, Patters AB, Chesney RW (2002) Transcriptional repression of taurine transporter gene (TauT) by p53 in renal cells. J Biol Chem 277:39266–39273PubMedCrossRefGoogle Scholar
  7. Harada H, Cusack BJ, Olson RD, Stroo W, Azuma J, Hamaguchi T, Schaffer SW (1990) Taurine deficiency and doxorubicin: interaction with the cardiac sarcolemmal calcium pump. Biochem Pharmacol 39:745–751PubMedCrossRefGoogle Scholar
  8. Heller-Stilb B, van Roeyen C, Rascher K, Hartwig HG, Huth A, Seeliger MW, Warskulat U, Haussinger D (2002) Disruption of the taurine transporter gene (taut) leads to retinal degeneration in mice. Faseb J 16:231–233PubMedGoogle Scholar
  9. Ho SN (2003) The role of NFAT5/TonEBP in establishing an optimal intracellular environment. Arch Biochem Biophys 413:151–157PubMedCrossRefGoogle Scholar
  10. Huxtable R, Bressler R (1974) Taurine concentrations in congestive heart failure. Science 184:1187–1188PubMedCrossRefGoogle Scholar
  11. Huxtable RJ (1992) Physiological actions of taurine. Physiol Rev 72:101–163PubMedGoogle Scholar
  12. Ito H, Miller SC, Billingham ME, Akimoto H, Torti SV, Wade R, Gahlmann R, Lyons G, Kedes L, Torti FM (1990) Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro. Proc Natl Acad Sci USA 87:4275–4279PubMedCrossRefGoogle Scholar
  13. Ito T, Fujio Y, Hirata M, Takatani T, Matsuda T, Muraoka S, Takahashi K, Azuma J (2004) Expression of taurine transporter is regulated through the TonE (tonicity-responsive element)/TonEBP (TonE-binding protein) pathway and contributes to cytoprotection in HepG2 cells. Biochem J 382:177–182PubMedCrossRefGoogle Scholar
  14. Ito T, Fujio Y, Takahashi K, Azuma J (2007) Degradation of NFAT5, a transcriptional regulator of osmotic stress-related genes, is a critical event for doxorubicin-induced cytotoxicity in cardiac myocytes. J Biol Chem 282:1152–1160PubMedCrossRefGoogle Scholar
  15. Ko BC, Turck CW, Lee KW, Yang Y, Chung SS (2000) Purification, identification, and characterization of an osmotic response element binding protein. Biochem Biophys Res Commun 270:52–61PubMedCrossRefGoogle Scholar
  16. Kumarapeli AR, Horak KM, Glasford JW, Li J, Chen Q, Liu J, Zheng H, Wang X (2005) A novel transgenic mouse model reveals deregulation of the ubiquitin-proteasome system in the heart by doxorubicin. Faseb J 19:2051–2053PubMedGoogle Scholar
  17. Lopez-Rodriguez C, Antos CL, Shelton JM, Richardson JA, Lin F, Novobrantseva TI, Bronson RT, Igarashi P, Rao A, Olson EN (2004) Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression. Proc Natl Acad Sci USA 101:2392–2397PubMedCrossRefGoogle Scholar
  18. Maouyo D, Kim JY, Lee SD, Wu Y, Woo SK, Kwon HM (2002) Mouse TonEBP-NFAT5: expression in early development and alternative splicing. Am J Physiol Renal Physiol 282:F802–F809PubMedGoogle Scholar
  19. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229PubMedCrossRefGoogle Scholar
  20. Miyakawa H, Woo SK, Chen CP, Dahl SC, Handler JS, Kwon HM (1998) Cis- and trans-acting factors regulating transcription of the BGT1 gene in response to hypertonicity. Am J Physiol 274:F753–F761PubMedGoogle Scholar
  21. Moise NS, Pacioretty LM, Kallfelz FA, Stipanuk MH, King JM, Gilmour RF, Jr. (1991) Dietary taurine deficiency and dilated cardiomyopathy in the fox. Am Heart J 121:541–547PubMedCrossRefGoogle Scholar
  22. Oudit GY, Trivieri MG, Khaper N, Husain T, Wilson GJ, Liu P, Sole MJ, Backx PH (2004) Taurine supplementation reduces oxidative stress and improves cardiovascular function in an iron-overload murine model. Circulation 109:1877–1885PubMedCrossRefGoogle Scholar
  23. Pion PD, Kittleson MD, Rogers QR, Morris JG (1987) Myocardial failure in cats associated with low plasma taurine: a reversible cardiomyopathy. Science 237:764–768PubMedCrossRefGoogle Scholar
  24. Poizat C, Sartorelli V, Chung G, Kloner RA, Kedes L (2000) Proteasome-mediated degradation of the coactivator p300 impairs cardiac transcription. Mol Cell Biol 20:8643–8654PubMedCrossRefGoogle Scholar
  25. Rim JS, Atta MG, Dahl SC, Berry GT, Handler JS, Kwon HM (1998) Transcription of the sodium/myo-inositol cotransporter gene is regulated by multiple tonicity-responsive enhancers spread over 50 kilobase pairs in the 5’-flanking region. J Biol Chem 273:20615–20621PubMedCrossRefGoogle Scholar
  26. Satoh H, Sperelakis N (1998) Review of some actions of taurine on ion channels of cardiac muscle cells and others. Gen Pharmacol 30:451–463PubMedCrossRefGoogle Scholar
  27. Schaffer SW, Azuma J, Takahashi K, Mozaffari M (2003) Why is taurine cytoprotective? Adv Exp Med Biol 526:307–321PubMedGoogle Scholar
  28. Schaffer SW, Solodushko V, Azuma J (2000a) Taurine-deficient cardiomyopathy: role of phospholipids, calcium and osmotic stress. Adv Exp Med Biol 483:57–69CrossRefGoogle Scholar
  29. Schaffer SW, Takahashi K, Azuma J (2000b) Role of osmoregulation in the actions of taurine. Amino Acids 19:527–546CrossRefGoogle Scholar
  30. Singal PK, Iliskovic N (1998) Doxorubicin-induced cardiomyopathy. N Engl J Med 339:900–905PubMedCrossRefGoogle Scholar
  31. Takahashi K, Ohyabu Y, Solodushko V, Takatani T, Itoh T, Schaffer SW,Azuma J (2003) Taurine renders the cell resistant to ischemia-induced injury in cultured neonatal rat cardiomyocytes. J Cardiovasc Pharmacol 41:726–733PubMedCrossRefGoogle Scholar
  32. Takatani T, Takahashi K, Uozumi Y, Matsuda T, Ito T, Schaffer SW, Fujio Y, Azuma J (2004) Taurine prevents the ischemia-induced apoptosis in cultured neonatal rat cardiomyocytes through Akt/caspase-9 pathway. Biochem Biophys Res Commun 316:484–489PubMedCrossRefGoogle Scholar
  33. Takihara K, Azuma J, Awata N, Ohta H, Hamaguchi T, Sawamura A, Tanaka Y, Kishimoto S, Sperelakis N (1986) Beneficial effect of taurine in rabbits with chronic congestive heart failure. Am Heart J 112:1278–1284PubMedCrossRefGoogle Scholar
  34. Trama J, Go WY, Ho SN (2002) The osmoprotective function of the NFAT5 transcription factor in T cell development and activation. J Immunol 169:5477–5488PubMedGoogle Scholar
  35. Trama J, Lu Q, Hawley RG, Ho SN (2000) The NFAT-related protein NFATL1 (TonEBP/NFAT5) is induced upon T cell activation in a calcineurin-dependent manner. J Immunol 165:4884–4894PubMedGoogle Scholar
  36. Uchida S, Kwon HM, Yamauchi A, Preston AS, Marumo F, Handler JS (1992) Molecular cloning of the cDNA for an MDCK cell Na(+)- and Cl(-)-dependent taurine transporter that is regulated by hypertonicity. Proc Natl Acad Sci USA 89:8230–8234PubMedCrossRefGoogle Scholar
  37. Uozumi Y, Ito T, Hoshino Y, Mohri T, Maeda M, Takahashi K, Fujio Y, Azuma J (2006) Myogenic differentiation induces taurine transporter in association with taurine-mediated cytoprotection in skeletal muscles. Biochem J 394:699–706PubMedCrossRefGoogle Scholar
  38. Wang Y, Ko BC, Yang JY, Lam TT, Jiang Z, Zhang J, Chung SK, Chung SS (2005) Transgenic mice expressing dominant-negative osmotic-response element-binding protein (OREBP) in lens exhibit fiber cell elongation defect associated with increased DNA breaks. J Biol Chem 280:19986–19991PubMedCrossRefGoogle Scholar
  39. Woo SK, Lee SD, Kwon HM (2002) TonEBP transcriptional activator in the cellular response to increased osmolality. Pflugers Arch 444:579–585PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Takashi Ito
    • 1
  • Yasushi Fujio
  • Stephen W. Schaffer
  • Junichi Azuma
  1. 1.Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical SciencesOsaka UniversityJapan

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