scholarly journals Thyroid Hormone Induces Cardiac Myocyte Hypertrophy in a Thyroid Hormone Receptor α1-Specific Manner that Requires TAK1 and p38 Mitogen-Activated Protein Kinase

2005 ◽  
Vol 19 (6) ◽  
pp. 1618-1628 ◽  
Author(s):  
Koichiro Kinugawa ◽  
Mark Y. Jeong ◽  
Michael R. Bristow ◽  
Carlin S. Long
Keyword(s):  
Thyroid Hormone ◽  
Protein Kinase ◽  
Hormone Receptor ◽  
Cardiac Myocyte ◽  
Thyroid Hormone Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Myocyte Hypertrophy ◽  
Specific Manner ◽  
Mitogen Activated Protein ◽  
Cardiac Myocyte Hypertrophy

scholarly journals The Trifunctional Protein Mediates Thyroid Hormone Receptor-Dependent Stimulation of Mitochondria Metabolism

2012 ◽  
Vol 26 (7) ◽  
pp. 1117-1128 ◽  
Author(s):  
E. Sandra Chocron ◽  
Naomi L. Sayre ◽  
Deborah Holstein ◽  
Nuttawut Saelim ◽  
Jamal A. Ibdah ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Thyroid Hormone ◽  
Protein Kinase ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Mitochondrial Metabolism ◽  
Dependent Manner ◽  
Compound C ◽  
Amp Activated Protein Kinase ◽  
Stimulation Of

Abstract We previously demonstrated that the thyroid hormone, T3, acutely stimulates mitochondrial metabolism in a thyroid hormone receptor (TR)-dependent manner. T3 has also recently been shown to stimulate mitochondrial fatty acid oxidation (FAO). Here we report that TR-dependent stimulation of metabolism is mediated by the mitochondrial trifunctional protein (MTP), the enzyme responsible for long-chain FAO. Stimulation of FAO was significant in cells that expressed a nonnuclear amino terminus shortened TR isoform (sTR43) but not in adult fibroblasts cultured from mice deficient in both TRα and TRβ isoforms (TRα−/−β−/−). Mouse embryonic fibroblasts deficient in MTP (MTP−/−) did not support T3-stimulated FAO. Inhibition of fatty-acid trafficking into mitochondria using the AMP-activated protein kinase inhibitor 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyrrazolo[1,5-a]-pyrimidine (compound C) or the carnitine palmitoyltransferase 1 inhibitor etomoxir prevented T3-stimulated FAO. However, T3 treatment could increase FAO when AMP-activated protein kinase was maximally activated, indicating an alternate mechanism of T3-stimulated FAO exists, even when trafficking is presumably high. MTPα protein levels and higher molecular weight complexes of MTP subunits were increased by T3 treatment. We suggest that T3-induced increases in mitochondrial metabolism are at least in part mediated by a T3-shortened TR isoform-dependent stabilization of the MTP complex, which appears to lower MTP subunit turnover.

Nuclear localization of protein kinase C-α induces thyroid hormone receptor-α1 expression in the cardiomyocyte

2006 ◽  
Vol 290 (1) ◽  
pp. H381-H389 ◽  
Author(s):  
Agnes Kenessey ◽  
Elizabeth Ann Sullivan ◽  
Kaie Ojamaa
Keyword(s):  
Protein Kinase C ◽  
Thyroid Hormone ◽  
Protein Kinase ◽  
Nuclear Localization ◽  
Hormone Receptor ◽  
Nuclear Translocation ◽  
Thyroid Hormone Receptor ◽  
Neonatal Rat ◽  
Cardiac Phenotype ◽  
Kinase C

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) PKCα or constitutively active (ca) PKCδ and PKCε. Overexpression of wtPKCα, but not caPKCδ or caPKCε, induced a 28-fold increase ( P < 0.001) in TRα1 protein in the nuclear compartment and a smaller increase in the cytosol. Furthermore, TRα1 mRNA was increased 55-fold ( P < 0.001). This effect of PKCα was dependent on its kinase activity because dnPKCα was without effect. Phorbol 12-myristate 13-acetate (PMA) induced nuclear translocation of endogenous PKCα and Ad-wtPKCα concomitantly with an increase in nuclear TRα1 protein. In contrast, PMA-induced nuclear translocation of dnPKCα resulted in a decrease of TRα1. The increase in TRα1 protein in Ad-wtPKCα-transduced cardiomyocytes was not the result of a reduced rate of protein degradation, nor was the half-life of TRα1 mRNA prolonged, suggesting a PKCα-mediated effect on TRα transcription. Although phosphorylation of ERK1/2 was increased in Ad-wtPKCα-transduced cells, inhibition of phospho-ERK did not change TRα1 expression. PKCα overexpression in cardiomyocytes caused marked repression of triiodothyronine (T3)-responsive genes, α-myosin heavy chain, and the sarcoplasmic reticulum calcium-activated adenosinetriphosphatase SERCA2. Treatment with T3 for 4 h resulted in significant reductions of PKCα in nuclear and cytosolic compartments, and decreased TRα1 mRNA and protein, with normalization of phenotype. These results implicate PKCα as a regulator of TR function and suggest that nuclear localization of PKCα may control transcription of the TRα gene, and consequently, affect cardiac phenotype.

scholarly journals MED1 Phosphorylation Promotes Its Association with Mediator: Implications for Nuclear Receptor Signaling

2008 ◽  
Vol 28 (12) ◽  
pp. 3932-3942 ◽  
Author(s):  
Madesh Belakavadi ◽  
Pradeep K. Pandey ◽  
Ravi Vijayvargia ◽  
Joseph D. Fondell
Keyword(s):  
Rna Polymerase Ii ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Nuclear Hormone Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Erk Phosphorylation ◽  
Broad Array ◽  
Mitogen Activated Protein

ABSTRACT Mediator is a conserved multisubunit complex that acts as a functional interface between regulatory transcription factors and the general RNA polymerase II initiation apparatus. MED1 is a pivotal component of the complex that binds to nuclear receptors and a broad array of other gene-specific activators. Paradoxically, MED1 is found in only a fraction of the total cellular Mediator complexes, and the mechanisms regulating its binding to the core complex remain unclear. Here, we report that phosphorylation of MED1 by mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) promotes its association with Mediator. We show that MED1 directly binds to the MED7 subunit and that ERK phosphorylation of MED1 enhances this interaction. Interestingly, we found that both thyroid and steroid hormones stimulate MED1 phosphorylation in vivo and that MED1 phosphorylation is required for its nuclear hormone receptor coactivator activity. Finally, we show that MED1 phosphorylation by ERK enhances thyroid hormone receptor-dependent transcription in vitro. Our findings suggest that ERK phosphorylation of MED1 is a regulatory mechanism that promotes MED1 association with Mediator and, as such, may facilitate a novel feed-forward action of nuclear hormones.

scholarly journals Role of 14-3-3-Mediated p38 Mitogen-Activated Protein Kinase Inhibition in Cardiac Myocyte Survival

2003 ◽  
Vol 93 (11) ◽  
pp. 1026-1028 ◽  
Author(s):  
Shaosong Zhang ◽  
Jie Ren ◽  
Cindy E. Zhang ◽  
Ilya Treskov ◽  
Yibin Wang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Myocyte ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Inhibition ◽  
Protein Kinase Inhibition ◽  
Mitogen Activated Protein

scholarly journals Stimulation of the p38 Mitogen-activated Protein Kinase Pathway in Neonatal Rat Ventricular Myocytes by the G Protein–coupled Receptor Agonists, Endothelin-1 and Phenylephrine: A Role in Cardiac Myocyte Hypertrophy?

1998 ◽  
Vol 142 (2) ◽  
pp. 523-535 ◽  
Author(s):  
Angela Clerk ◽  
Ashour Michael ◽  
Peter H. Sugden
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Cardiac Myocyte ◽  
Mapk Pathway ◽  
Morphological Changes ◽  
Mitogen Activated Protein Kinase ◽  
Neonatal Rat ◽  
Endothelin 1 ◽  
P38 Mapk Pathway ◽  
Cardiac Myocyte Hypertrophy

We examined the activation of the p38 mitogen-activated protein kinase (p38-MAPK) pathway by the G protein–coupled receptor agonists, endothelin-1 and phenylephrine in primary cultures of cardiac myocytes from neonatal rat hearts. Both agonists increased the phosphorylation (activation) of p38-MAPK by ∼12-fold. A p38-MAPK substrate, MAPK-activated protein kinase 2 (MAPKAPK2), was activated approximately fourfold and 10 μM SB203580, a p38-MAPK inhibitor, abolished this activation. Phosphorylation of the MAPKAPK2 substrate, heat shock protein 25/27, was also increased. Using selective inhibitors, activation of the p38-MAPK pathway by endothelin-1 was shown to involve protein kinase C but not Gi/Go nor the extracellularly responsive kinase (ERK) pathway. SB203580 failed to inhibit the morphological changes associated with cardiac myocyte hypertrophy induced by endothelin-1 or phenylephrine between 4 and 24 h. However, it decreased the myofibrillar organization and cell profile at 48 h. In contrast, inhibition of the ERK cascade with PD98059 prevented the increase in myofibrillar organization but not cell profile. These data are not consistent with a role for the p38-MAPK pathway in the immediate induction of the morphological changes of hypertrophy but suggest that it may be necessary over a longer period to maintain the response.

scholarly journals Augmentation of Thyroid Hormone Receptor-Mediated Transcription by Ca2+/Calmodulin-Dependent Protein Kinase Type IV

Endocrinology ◽  
2000 ◽  
Vol 141 (6) ◽  
pp. 2275-2278 ◽  
Author(s):  
Momoyo Kuno-Murata ◽  
Noriyuki Koibuchi ◽  
Harumi Fukuda ◽  
Mitsunobu Murata ◽  
William W. Chin
Keyword(s):  
Thyroid Hormone ◽  
Protein Kinase ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Dependent Protein Kinase ◽  
Type Iv ◽  
Dependent Protein

scholarly journals cGMP-dependent Protein Kinase Type I Inhibits TAB1-p38 Mitogen-activated Protein Kinase Apoptosis Signaling in Cardiac Myocytes

2006 ◽  
Vol 281 (43) ◽  
pp. 32831-32840 ◽  
Author(s):  
Beate Fiedler ◽  
Robert Feil ◽  
Franz Hofmann ◽  
Christian Willenbockel ◽  
Helmut Drexler ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Myocytes ◽  
P38 Mapk ◽  
Cardiac Myocyte ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Mapk Phosphorylation ◽  
Mitogen Activated Protein ◽  
Dependent Protein

Cardiac myocyte apoptosis during ischemia and reperfusion (I/R) is tightly controlled by a complex network of stress-responsive signaling pathways. One pro-apoptotic pathway involves the interaction of the scaffold protein TAB1 with p38 mitogen-activated protein kinase (p38 MAPK) leading to the autophosphorylation and activation of p38 MAPK. Conversely, NO and its second messenger cGMP protect cardiac myocytes from apoptosis during I/R. We provide evidence that the cGMP target cGMP-dependent protein kinase type I (PKG I) interferes with TAB1-p38 MAPK signaling to protect cardiac myocytes from I/R injury. In isolated neonatal cardiac myocytes, activation of PKG I inhibited the interaction of TAB1 with p38 MAPK, p38 MAPK phosphorylation, and apoptosis induced by simulated I/R. During I/R in vivo, mice with a cardiac myocyte-restricted deletion of PKG I displayed a more pronounced interaction of TAB1 with p38 MAPK and a stronger phosphorylation of p38 MAPK in the myocardial area at risk during reperfusion and more apoptotic cardiac myocytes in the infarct border zone as compared with wild-type littermates. Notably, adenoviral expression of a constitutively active PKG I mutant truncated at the N terminus(PKGI-ΔN1-92) did not inhibit p38 MAPK phosphorylation and apoptosis induced by simulated I/R in vitro, indicating that the N terminus of PKG I is required. As shown by co-immunoprecipitation experiments in HEK293 cells, cGMP-activated PKG I, but not constitutively active PKG I-ΔN1-92 or PKG I mutants carrying point mutations in the N-terminal leucine-isoleucine zipper, interacted with p38 MAPK, and prevented the binding of TAB1 to p38 MAPK. Together, our data identify a novel interaction between the cGMP target PKG I and the TAB1-p38 MAPK signaling pathway that serves as a defense mechanism against myocardial I/R injury.

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