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 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.

The functional relationship between co-repressor N-CoR and SMRT in mediating transcriptional repression by thyroid hormone receptor α

2008 ◽  
Vol 411 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Kyung-Chul Choi ◽  
So-Young Oh ◽  
Hee-Bum Kang ◽  
Yoo-Hyun Lee ◽  
Seungjoo Haam ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Transcriptional Repression ◽  
Fatty Acid Synthase ◽  
Hormone Receptors ◽  
Target Genes ◽  
Functional Relationship ◽  
Thyroid Hormone Receptor ◽  
B Cell Lymphoma ◽  
Hormone Response Elements

A central issue in mediating repression by nuclear hormone receptors is the distinct or redundant function between co-repressors N-CoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptor). To address the functional relationship between SMRT and N-CoR in TR (thyroid hormone receptor)-mediated repression, we have identified multiple TR target genes, including BCL3 (B-cell lymphoma 3-encoded protein), Spot14 (thyroid hormone-inducible hepatic protein), FAS (fatty acid synthase), and ADRB2 (β-adrenergic receptor 2). We demonstrated that siRNA (small interfering RNA) treatment against either N-CoR or SMRT is sufficient for the de-repression of multiple TR target genes. By the combination of sequence mining and physical association as determined by ChIP (chromatin immunoprecipitation) assays, we mapped the putative TREs (thyroid hormone response elements) in BCL3, Spot14, FAS and ADRB2 genes. Our data clearly show that SMRT and N-CoR are independently recruited to various TR target genes. We also present evidence that overexpression of N-CoR can restore repression of endogenous genes after knocking down SMRT. Finally, unliganded, co-repressor-free TR is defective in repression and interacts with a co-activator, p300. Collectively, these results suggest that both SMRT and N-CoR are limited in cells and that knocking down either of them results in co-repressor-free TR and consequently de-repression of TR target genes.

scholarly journals Activation of Phosphatidylinositol 3-Kinase Signaling Promotes Aberrant Pituitary Growth in a Mouse Model of Thyroid-Stimulating Hormone-Secreting Pituitary Tumors

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3339-3345 ◽  
Author(s):  
Changxue Lu ◽  
Mark C. Willingham ◽  
Fumihiko Furuya ◽  
Sheue-yann Cheng
Keyword(s):  
Cell Proliferation ◽  
Mouse Model ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Specific Inhibitor ◽  
Pituitary Tumors ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

TSH-secreting pituitary tumors (TSHomas) are pituitary tumors that constitutively secrete TSH. Molecular mechanisms underlying this abnormality are largely undefined. We recently created a knock-in mutant mouse harboring a mutation (denoted as PV) in the thyroid hormone receptor-β gene (TRβPV/PV mouse). As these mice age, they spontaneously develop TSHomas. Using this mouse model, we investigated the role of the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway in the pathogenesis of TSHomas. Concurrent with aberrant growth of pituitaries, AKT and its downstream effectors, mammalian target rapamycin and p70S6K, were activated to contribute to increased cell proliferation and pituitary growth. In addition, activation of AKT led to decreased apoptosis by inhibiting proapoptotic activity of Bcl-2-associated death promoter, further contributing to the aberrant cell proliferation. These results suggest an activated PI3K-AKT pathway could underscore tumorigenesis, raising the possibility that this pathway could be a potential therapeutic target in TSHomas. Indeed, TRβPV/PV mice treated with a PI3K-specific inhibitor, LY294002, showed a significant decrease in pituitary growth. The progrowth signaling via AKT-mammalian target rapamycin-p70S6K and cyclin D1/cyclin-dependent kinase were inhibited, and proapoptotic activity of Bcl-2-associated death promoter was increased by LY294002 treatment. Thus, activation of the PI3K-AKT pathway mediates, at least in part, the aberrant pituitary growth, and the intervention of this signaling pathway presents a novel therapeutic opportunity for TSHomas.

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 A Rapid Cytoplasmic Mechanism for PI3 Kinase Regulation by the Nuclear Thyroid Hormone Receptor, TRβ, and Genetic Evidence for Its Role in the Maturation of Mouse Hippocampal Synapses In Vivo

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3713-3724 ◽  
Author(s):  
Negin P. Martin ◽  
Ezequiel Marron Fernandez de Velasco ◽  
Fengxia Mizuno ◽  
Erica L. Scappini ◽  
Bernd Gloss ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Zinc Finger ◽  
Hormone Receptor ◽  
Mammalian Cells ◽  
Thyroid Hormone Receptor ◽  
Signaling Mechanism ◽  
Rapid Signaling ◽  
Phosphatidylinositol 3

Abstract Several rapid physiological effects of thyroid hormone on mammalian cells in vitro have been shown to be mediated by the phosphatidylinositol 3-kinase (PI3K), but the molecular mechanism of PI3K regulation by nuclear zinc finger receptor proteins for thyroid hormone and its relevance to brain development in vivo have not been elucidated. Here we show that, in the absence of hormone, the thyroid hormone receptor TRβ forms a cytoplasmic complex with the p85 subunit of PI3K and the Src family tyrosine kinase, Lyn, which depends on two canonical phosphotyrosine motifs in the second zinc finger of TRβ that are not conserved in TRα. When hormone is added, TRβ dissociates and moves to the nucleus, and phosphatidylinositol (3, 4, 5)-trisphosphate production goes up rapidly. Mutating either tyrosine to a phenylalanine prevents rapid signaling through PI3K but does not prevent the hormone-dependent transcription of genes with a thyroid hormone response element. When the rapid signaling mechanism was blocked chronically throughout development in mice by a targeted point mutation in both alleles of Thrb, circulating hormone levels, TRβ expression, and direct gene regulation by TRβ in the pituitary and liver were all unaffected. However, the mutation significantly impaired maturation and plasticity of the Schaffer collateral synapses on CA1 pyramidal neurons in the postnatal hippocampus. Thus, phosphotyrosine-dependent association of TRβ with PI3K provides a potential mechanism for integrating regulation of development and metabolism by thyroid hormone and receptor tyrosine kinases.

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