scholarly journals Thyroid hormone receptor TRβ1 mediates Akt activation by T3 in pancreatic β cells

2007 ◽  
Vol 38 (2) ◽  
pp. 221-233 ◽  
Author(s):  
Cecilia Verga Falzacappa ◽  
Eleonora Petrucci ◽  
Valentina Patriarca ◽  
Simona Michienzi ◽  
Antonio Stigliano ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Nuclear Translocation ◽  
Thyroid Hormone Receptor ◽  
Phosphatidylinositol 3 Kinase ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Akt Activation ◽  
Biological Responses ◽  
Confocal Immunofluorescence

It has recently been recognized that thyroid hormones may rapidly generate biological responses by non-genomic mechanisms that are unaffected by inhibitors of transcription and translation. The signal transduction pathways underlying these effects are just beginning to be defined. We demonstrated that thyroid hormone T3 rapidly induces Akt activation in pancreatic β cells rRINm5F and hCM via thyroid hormone receptor (TR) β1. The phosphorylation of Akt was T3 specific and dependent. Coimmunoprecipitation and colocalization experiments revealed that the phosphatidylinositol 3 kinase (PI3K) p85α subunit and the thyroid receptor β1 were able to form a complex at the cytoplasmic level in both the cell lines, suggesting that a ‘cytoplasmic TRβ1’ was implicated. Moreover, we evidenced that T3 treatment was able to induce kinase activity of the TRβ1-associated PI3K. The silencing of TRβ1 expression through RNAi confirmed this receptor to be crucial for the T3-induced activation of Akt. This action involved a T3-induced nuclear translocation of activated Akt, as demonstrated by confocal immunofluorescence. In summary, T3 is able to specifically activate Akt in the islet β cells rRINm5F and hCM through the interaction between TRβ1 and PI3K p85α, demonstrating the involvement of TRβ1 in this novel T3 non-genomic action in islet β cells.

scholarly journals Liganded Thyroid Hormone Receptor-α Enhances Proliferation of Pancreatic β-Cells

2010 ◽  
Vol 285 (32) ◽  
pp. 24477-24486 ◽  
Author(s):  
Fumihiko Furuya ◽  
Hiroki Shimura ◽  
Sayaka Yamashita ◽  
Toyoshi Endo ◽  
Tetsuro Kobayashi
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Thyroid Hormone Receptor Α

scholarly journals Nuclear Translocation of MEK1 Triggers a Complex T Cell Response through the Corepressor Silencing Mediator of Retinoid and Thyroid Hormone Receptor

2012 ◽  
Vol 190 (1) ◽  
pp. 159-167 ◽  
Author(s):  
Lei Guo ◽  
Chaoyu Chen ◽  
Qiaoling Liang ◽  
Mohammad Zunayet Karim ◽  
Magdalena M. Gorska ◽  
...  
Keyword(s):  
T Cell ◽  
Thyroid Hormone ◽  
Cell Response ◽  
Hormone Receptor ◽  
Nuclear Translocation ◽  
Thyroid Hormone Receptor ◽  
T Cell Response

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 Thyroid hormone mediated changes in gene expression can be initiated by cytosolic action of the thyroid hormone receptor β through the phosphatidylinositol 3-kinase pathway

2006 ◽  
Vol 4 (1) ◽  
pp. nrs.04020 ◽  
Author(s):  
Lars C. Moeller ◽  
Xia Cao ◽  
Alexandra M. Dumitrescu ◽  
Hisao Seo ◽  
Samuel Refetoff
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Dna Sequences ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Monocarboxylate Transporter ◽  
Receptor Interaction ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

Thyroid hormone (TH) action is mediated principally through binding of the hormone ligand, 3,3,5-triiodothyronine (T3), to TH receptors (TRs). This hormone-receptor interaction recruits other proteins to form complexes that regulate gene expression by binding to DNA sequences in the promoter of target genes. We recently described an extranuclear mechanism of TH action that consists of the association of TH-liganded TRβ with p85α [regulatory subunit of phosphatidylinositol 3-kinase (PI3K)] in the cytosol and subsequent activation of the PI3K, generating phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3]. This initiates the activation of a signaling cascade by phosphorylation of Akt, mammalian target of rapamycin (mTOR) and its substrate p70S6K, leading to the stimulation of ZAKI-4α synthesis, a calcineurin inhibitor. Furthermore, we found that this same mechanism leads to induction of the transcription factor hypoxia-inducible factor (HIF-1α), and its target genes, glucose transporter (GLUT)1, platelet-type phosphofructokinase (PFKP), and monocarboxylate transporter (MCT) 4. These genes are of special interest, because their products have important roles in cellular glucose metabolism, from glucose uptake (GLUT1) to glycolysis (PFKP) and lactate export (MCT4). These results demonstrate that the TH-TRβ complex can exert a non-genomic action in the cytosol leading to changes in gene expression by direct (HIF-1α) and indirect (ZAKI-4α, GLUT1, PFKP) means.

scholarly journals Triiodothyronine utilizes phosphatidylinositol 3-kinase pathway to activate anti-apoptotic myeloid cell leukemia-1

2008 ◽  
Vol 41 (3) ◽  
pp. 177-186 ◽  
Author(s):  
Maciej Pietrzak ◽  
Monika Puzianowska-Kuznicka
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Cell Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Hek 293 ◽  
Phosphatidylinositol 3

Triiodothyronine (T3) regulates apoptosis in cells according to their developmental stage, cell type, and pathophysiological state. The molecular mechanisms of this regulation, however, have been largely unknown. In this work, we show that the expression of the myeloid cell leukemia-1 (MCL-1) protein, an anti-apoptotic member of B-cell lymphoma-2 (BCL-2) family, increases in thyroid hormone receptor-expressing human kidney-2 (HK2) cells upon 6-h incubation in 100 nM T3; we also describe the molecular mechanisms leading to this phenomenon. Transcription regulation assays performed in human embryonic kidney (HEK) 293 cells show that 100 nM T3 increases transcription from the MCL-1 promoter twofold in the presence of thyroid hormone receptor β1, but not of its α1 isoform. However, this increase is not a result of direct activation via the thyroid hormone-response element, TRE-DR4, located at the −998 to −983 position in this promoter; furthermore, the presence of 9-cis-retinoic acid receptor is not required. The promoter's activation is abolished in the presence of phosphatidylinositol 3-kinase (PI3-K) inhibitor, wortmannin. The −295 to −107 promoter fragment contains all sequences involved in T3-dependent activation of the MCL-1 promoter, and cAMP-responsive element located at the −262 to −255 position is a major mediator in this process. Therefore, MCL-1 expression is activated by T3, which increases its promoter activity by a non-genomic mechanism using the PI3-K signal transduction pathway. We propose that this is another mechanism by which T3 regulates apoptosis.

scholarly journals p43, a Truncated Form of Thyroid Hormone Receptor α, Regulates Maturation of Pancreatic β Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2489
Author(s):  
Emilie Blanchet ◽  
Laurence Pessemesse ◽  
Christine Feillet-Coudray ◽  
Charles Coudray ◽  
Chantal Cabello ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Insulin Secretion ◽  
Thyroid Hormone ◽  
Pancreatic Islet ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Β Cells ◽  
Β Cell ◽  
Truncated Form ◽  
Thyroid Hormone Receptor Α

P43 is a truncated form of thyroid hormone receptor α localized in mitochondria, which stimulates mitochondrial respiratory chain activity. Previously, we showed that deletion of p43 led to reduction of pancreatic islet density and a loss of glucose-stimulated insulin secretion in adult mice. The present study was designed to determine whether p43 was involved in the processes of β cell development and maturation. We used neonatal, juvenile, and adult p43-/- mice, and we analyzed the development of β cells in the pancreas. Here, we show that p43 deletion affected only slightly β cell proliferation during the postnatal period. However, we found a dramatic fall in p43-/- mice of MafA expression (V-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog A), a key transcription factor of beta-cell maturation. Analysis of the expression of antioxidant enzymes in pancreatic islet and 4-hydroxynonenal (4-HNE) (a specific marker of lipid peroxidation) staining revealed that oxidative stress occurred in mice lacking p43. Lastly, administration of antioxidants cocktail to p43-/- pregnant mice restored a normal islet density but failed to ensure an insulin secretion in response to glucose. Our findings demonstrated that p43 drives the maturation of β cells via its induction of transcription factor MafA during the critical postnatal window.

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