Thyroid hormone action at the cellular, genomic and target gene levels

Yen, Paul M.; Ando, Shinichiro; Feng, Xu; Liu, Ying; Maruvada, Padma; Xia, Xianmin

doi:10.1016/j.mce.2005.11.030

Cited by 198 publications

(158 citation statements)

References 31 publications

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“…The genomic actions of thyroid hormone involve primary interaction of the hormone T 3 in the cell nucleus with a heterodimer of TR␤1 and another member of the superfamily of hormone receptors such as retinoid X receptor to initiate transcription of thyroid hormone-responsive genes (41). The process involves the shedding of corepressor proteins and the recruitment of coactivators (1,25).…”

Section: Discussionmentioning

confidence: 99%

l-Thyroxine vs. 3,5,3′-triiodo-l-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

Lin¹,

Sun²,

Tang³

et al. 2009

American Journal of Physiology-Cell Physiology

234

236

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,5,3Ј-Triiodo-L-thyronine (T3), but not L-thyroxine (T4), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an ␣ v␤3 integrin receptor on human glioblastoma U-87 MG cells. Although both T 3 and T4 stimulated extracellular signal-regulated kinase (ERK) 1/2, activated ERK1/2 did not contribute to T 3-induced Src kinase or PI3-kinase activation, and an inhibitor of PI3-kinase, LY-294002, did not block activation of ERK1/2 by physiological concentrations of T 3 and T4. Thus the PI3-kinase, Src kinase, and ERK1/2 signaling cascades are parallel pathways in T 3-treated U-87 MG cells. T3 and T4 both caused proliferation of U-87 MG cells; these effects were blocked by the ERK1/2 inhibitor PD-98059 but not by LY-294002. Smallinterfering RNA knockdown of PI3-kinase confirmed that PI3-kinase was not involved in the proliferative action of T 3 on U-87 MG cells. PI3-kinase-dependent actions of T 3 in these cells included shuttling of nuclear thyroid hormone receptor-␣ (TR␣) from cytoplasm to nucleus and accumulation of hypoxia-inducible factor (HIF)-1␣ mRNA; LY-294002 inhibited these actions. Results of studies involving ␣v␤3 receptor antagonists tetraiodothyroacetic acid (tetrac) and Arg-Gly-Asp (RGD) peptide, together with mathematical modeling of the kinetics of displacement of radiolabeled T3 from the integrin by unlabeled T3 and by unlabeled T4, are consistent with the presence of two iodothyronine receptor domains on the integrin. A model proposes that one site binds T3 exclusively, activates PI3-kinase via Src kinase, and stimulates TR␣ trafficking and HIF-1␣ gene expression. Tetrac and RGD peptide both inhibit T3 action at this site. The second site binds T4 and T3, and, via this receptor, the iodothyronines stimulate ERK1/2-dependent tumor cell proliferation. T3 action here is inhibited by tetrac alone, but the effect of T4 is blocked by both tetrac and the RGD peptide. thyroid hormone; phosphatidylinositol 3-kinase; extracellular signal-regulated kinase 1/2; integrin ␣v␤3; glioblastoma cells; Src kinase; mitogenactivated protein kinase; intracellular hormone receptor trafficking ACTIONS OF THYROID HORMONE [L-thyroxine (T 4 ); 3,5,3Ј-triiodo-L-thyronine (T 3 )] that are independent of ligand binding to nuclear thyroid hormone receptors are called nongenomic actions. Nongenomic effects of thyroid hormone are initiated outside the cell nucleus but may culminate in complex cellular events that are nucleus mediated (7, 8, 26 -29). Initiation of nongenomic actions includes a plasma membrane receptor for T 4 and T 3 on integrin ␣ v ␤ 3 that is linked to mitogen-activated protein kinase [extracellular signal-regulated kinase (ERK) 1/2] for transduction of the hormone signal (3) and nuclear receptors residing in the cytosol of unstimulated cells, such as thyroid hormone receptor (TR) ␤1 (28).The phosphatidylinositol 3-kinase (PI3-kinase)/protein kinase B (Akt) pathway is an important regulator of cellular growth, metabolism, and survival (13, 19). Studies of Storey et al. (38) indi...

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Section: Discussionmentioning

confidence: 99%

l-Thyroxine vs. 3,5,3′-triiodo-l-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

Lin¹,

Sun²,

Tang³

et al. 2009

American Journal of Physiology-Cell Physiology

234

236

View full text Add to dashboard Cite

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“…The classical molecular mechanism of TH action involves uptake of TH by target cells, access of T3 to the cell nucleus and complexing of the hormone with nuclear TR, which sheds corepressors after binding of T3 and recruits coactivators to TREs and consequent hormone-responsive gene transcription, i.e. a genomic way (Yen et al, 2006). However, actions of TH in a variety of cells have been described that do not primarily involve nuclear TR (Davis et al, 2008) and thus are 'nongenomic'.…”

Section: Discussionmentioning

confidence: 99%

Low concentrations of bisphenol a suppress thyroid hormone receptor transcription through a nongenomic mechanism

Sheng

Tang

Liu

et al. 2012

Toxicology and Applied Pharmacology

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“…Similarly to other nuclear receptors, TR consists of a DNA-binding domain, ligand-binding domain and amino-terminal transactivation domain. The remaining non-hormone binding TR isoforms lack portions of the DNA-binding and/ or ligand-binding domains, and their functions are still unclear (20). In the nucleus, TRs recognize and bind to specific DNA sequences termed thyroid hormone response elements (TREs), located in the promoter region of target genes, and activate or repress transcription in response to T3 binding ( Figure 1).…”

Section: Thyroid Hormonesmentioning

confidence: 99%

“…It was originally believed that thyroid hormones, due to their lipophilic nature, enter target cells by passive diffusion. Currently, however, there is growing evidence indicating that T4 and T3 cross the plasma membrane by carrier mediated mechanisms (20,21). Several membrane transporter families have been identified, however only monocarboxylate transporter (MCT) 8, MCT 10 and organic anion-transporting polypeptides (OATPs) demonstrate a high degree of specificity towards thyroid hormone (22).…”

Section: Clinical Implications Of Altered Thyroid Functionmentioning

confidence: 99%

Clinical implications of altered thyroid status in male testicular function

Wajner

Wagner

Maia

2009

Arq Bras Endocrinol Metab

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Thyroid hormones are involved in the development and maintenance of virtually all tissues. Although for many years the testis was thought to be a thyroid-hormone unresponsive organ, studies of the last decades have demonstrated that thyroid dysfunction is associated not only with abnormalities in morphology and function of testes, but also with decreased fertility and alterations of sexual activity in men. Nowadays, the participation of triiodothyronine (T3) in the control of Sertoli and Leydig cell proliferation, testicular maturation, and steroidogenesis is widely accepted, as well as the presence of thyroid hormone transporters and receptors in testicular cells throughout the development process and in adulthood. But even with data suggesting that T3 may act directly on these cells to bring about its effects, there is still controversy regarding the impact of thyroid diseases on human spermatogenesis and fertility, which can be in part due to the lack of well-controlled clinical studies. The current review aims at presenting an updated picture of recent clinical data about the role of thyroid hormones in male gonadal function. RESUMOOs hormônios da tireoide estão envolvidos virtualmente no desenvolvimento e na manutenção de todos os tecidos. As gônadas masculinas foram, por décadas, consideradas insensíveis aos hormônios tireoidianos. No entanto, estudos mais recentes têm demonstrado que disfunções tireoidianas estão associadas não somente a anormalidades na morfologia e na função dos testículos, mas também à diminuição da fertilidade e alterações na atividade sexual masculina. Atualmente, o papel da triiodotironina (T3) no controle da proliferação das células de Sertoli e Leydig, maturação testicular e esteroidogênese é amplamente aceito, bem como a presença de transportadores e receptores para o hormônio tireoidiano nos testículos durante o período de desenvolvimento e a idade adulta. No entanto, apesar dos dados que indicam que o T3 atua diretamente nos testículos humanos, persistem controvérsias em relação ao impacto das doenças tireoidianas sobre a espermatogênese e a fertilidade, o que pode ser em parte devido à escassez de estudos clínicos nessa área. Essa revisão tem por objetivo apresentar um panorama de dados clínicos atualizados sobre o papel dos hormônios tireoidianos na função gonadal masculina. Arq Bras Endocrinol Metab. 2009;53(8):976-82 Descritores

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Thyroid hormone action at the cellular, genomic and target gene levels

Cited by 198 publications

References 31 publications

l-Thyroxine vs. 3,5,3′-triiodo-l-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

l-Thyroxine vs. 3,5,3′-triiodo-l-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

Low concentrations of bisphenol a suppress thyroid hormone receptor transcription through a nongenomic mechanism

Clinical implications of altered thyroid status in male testicular function

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