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This Article Full Text Full Text (PDF) All Versions of this Article: 288/2/H813    most recent 00804.2004v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Kenessey, A. Articles by Ojamaa, K. Search for Related Content PubMed PubMed Citation Articles by Kenessey, A. Articles by Ojamaa, K.

Ligand-mediated decrease of thyroid hormone receptor-₁ in cardiomyocytes by proteosome-dependent degradation and altered mRNA stability

¹North Shore-Long Island Jewish Research Institute and ²Departments of Cell Biology and Medicine, New York University School of Medicine, Manhasset, New York

Submitted 6 August 2004 ; accepted in final form 13 October 2004

Tri-iodo-L-thyronine (T₃) is essential for maintaining normal cardiac contractile function by regulating transcription of numerous T₃-responsive genes. Both hormone availability and relative amounts of nuclear thyroid hormone receptor isoforms (TR1, TR1) determine T₃ effectiveness. Cultured neonatal rat ventricular myocytes grown in T₃-depleted medium expressed predominantly TR1 protein, but within 4 h of T₃ treatment, TR1 protein increased significantly, whereas TR1 was decreased by 46 ± 5%. Using replication-defective adenoviruses to overexpress TR1 in cardiomyocytes, we studied the mechanisms by which T₃ mediated the decrease in TR1 protein. Inhibitors of the proteosome pathway resulted in an accumulation of ubiquitylated TR1 in the nucleus and prevented T₃-induced degradation of ubiquitylated TR1, suggesting that T₃ induced proteosome-mediated degradation of TR1; however, TR ubiquitylation was T₃ independent. TR1 transcriptional activity, measured using transient transfection of a thyroid hormone-responsive element (TRE) reporter plasmid, was T₃ dose dependent and inversely proportional to nuclear TR1 content, with 10 nM T₃ having maximum effect. Quantitative RT-PCR showed that both endogenous and adenovirus-expressed TR1 mRNAs were significantly decreased to 54 ± 11 and 25 ± 5%, respectively, within 4 h of T₃ treatment. Measurements of TR1 mRNA half-life in actinomycin D-treated cardiomyocytes showed that T₃ treatment significantly decreased TR1 mRNA half-life from 4 h to less than 2 h, whereas it had no effect of TR1 mRNA half-life. These data support a role for both the proteosome degradation pathway and altered mRNA stability in T₃-induced decrease of nuclear TR1 in the cardiomyocyte and provide novel cellular targets for therapeutic development.

neonatal rat ventricular myocyte; adenovirus; tri-iodo-L-thyronine; c-erbA

This article has been cited by other articles:

				A. Kenessey, E. A. Sullivan, and K. Ojamaa Nuclear localization of protein kinase C-{alpha} induces thyroid hormone receptor-{alpha}1 expression in the cardiomyocyte Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H381 - H389. [Abstract] [Full Text] [PDF]