Involvement of transcriptional factor TonEBP in the regulation of the taurine transporter in the cardiomyocyte.
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.
Ito
Takashi
T
Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Osaka University, Japan. takasy110@gmail.com
Fujio
Yasushi
Y
Schaffer
Stephen W
SW
Azuma
Junichi
J
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D004317:Doxorubicin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D011921:Rats, Inbred WKY; D013654:Taurine / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D000099247:Taurine Transporters
D004317:Doxorubicin; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D013654:Taurine; D014157:Transcription Factors; D000099247:Taurine Transporters; C492199:Nfat5 protein, rat