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Nuclear localization of protein kinase C- induces thyroid hormone receptor-1 expression in the cardiomyocyte

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

Submitted 1 June 2005 ; accepted in final form 2 September 2005

Maladaptive cardiac hypertrophy results in phenotypic changes in several genes that are thyroid hormone responsive, suggesting that thyroid hormone receptor (TR) function may be altered by cellular kinases, including protein kinase C (PKC) isozymes that are activated in pathological hypertrophy. To investigate the role of PKC signaling in regulating TR function, cultured neonatal rat ventricular myocytes were transduced with adenovirus (Ad) expressing wild-type (wt) or kinase-inactive (dn) PKC or constitutively active (ca) PKC and PKC. Overexpression of wtPKC, but not caPKC or caPKC, induced a 28-fold increase (P < 0.001) in TR1 protein in the nuclear compartment and a smaller increase in the cytosol. Furthermore, TR1 mRNA was increased 55-fold (P < 0.001). This effect of PKC was dependent on its kinase activity because dnPKC was without effect. Phorbol 12-myristate 13-acetate (PMA) induced nuclear translocation of endogenous PKC and Ad-wtPKC concomitantly with an increase in nuclear TR1 protein. In contrast, PMA-induced nuclear translocation of dnPKC resulted in a decrease of TR1. The increase in TR1 protein in Ad-wtPKC-transduced cardiomyocytes was not the result of a reduced rate of protein degradation, nor was the half-life of TR1 mRNA prolonged, suggesting a PKC-mediated effect on TR transcription. Although phosphorylation of ERK1/2 was increased in Ad-wtPKC-transduced cells, inhibition of phospho-ERK did not change TR1 expression. PKC overexpression in cardiomyocytes caused marked repression of triiodothyronine (T₃)-responsive genes, -myosin heavy chain, and the sarcoplasmic reticulum calcium-activated adenosinetriphosphatase SERCA2. Treatment with T₃ for 4 h resulted in significant reductions of PKC in nuclear and cytosolic compartments, and decreased TR1 mRNA and protein, with normalization of phenotype. These results implicate PKC as a regulator of TR function and suggest that nuclear localization of PKC may control transcription of the TR gene, and consequently, affect cardiac phenotype.

adenovirus; heart; triiodothyronine; extracellular signal-regulated kinase; sarcoplasmic reticulum calcium-activated adenosinetriphosphatase; myosin heavy chain

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