Cytosolic T3-binding protein modulates dynamic alteration of T3-mediated gene expression in cells

Takeshige, Keiko; Sekido, Takashi; Kitahara, Jun-ichirou; Ohkubo, Yousuke; Hiwatashi, Dai; Ishii, Hiroaki; Nishio, Shintaro; Takeda, Teiji; Komatsu, Mitsuhisa

doi:10.1507/endocrj.ej13-0418

Cited by 14 publications

(8 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4 F). These results indicate that DITPA may not be transported by μ-crystallin in the cell since its cellular levels are required for appropriate TH signaling ( Suzuki et al, 2007 , Takeshige et al, 2014 ). Considering that DIO3 , RARA and THRB were all upregulated in our GO analysis, it would suggest that TH signaling is maintained in these cell lines.…”

Section: Resultsmentioning

confidence: 98%

Overcoming Monocarboxylate Transporter 8 (MCT8)-Deficiency to Promote Human Oligodendrocyte Differentiation and Myelination

et al. 2017

View full text Add to dashboard Cite

Cell membrane thyroid hormone (TH) transport can be facilitated by the monocarboxylate transporter 8 (MCT8), encoded by the solute carrier family 16 member 2 (SLC16A2) gene. Human mutations of the gene, SLC16A2, result in the X-linked-inherited psychomotor retardation and hypomyelination disorder, Allan-Herndon-Dudley syndrome (AHDS). We posited that abrogating MCT8-dependent TH transport limits oligodendrogenesis and myelination. We show that human oligodendrocytes (OL), derived from the NKX2.1-GFP human embryonic stem cell (hESC) reporter line, express MCT8. Moreover, treatment of these cultures with DITPA (an MCT8-independent TH analog), up-regulates OL differentiation transcription factors and myelin gene expression. DITPA promotes hESC-derived OL myelination of retinal ganglion axons in co-culture. Pharmacological and genetic blockade of MCT8 induces significant OL apoptosis, impairing myelination. DITPA treatment limits OL apoptosis mediated by SLC16A2 down-regulation primarily signaling through AKT phosphorylation, driving myelination. Our results highlight the potential role of MCT8 in TH transport for human OL development and may implicate DITPA as a promising treatment for developmentally-regulated myelination in AHDS.

show abstract

Section: Resultsmentioning

confidence: 98%

Overcoming Monocarboxylate Transporter 8 (MCT8)-Deficiency to Promote Human Oligodendrocyte Differentiation and Myelination

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Contrary to earlier assumptions, T3 and T4 do not diffuse freely across the plasma membrane but are actively transported by specialized transport proteins, such as MCT8, MCT10, and OATP1C1 ( 65 ). Intracellular trafficking involves intracellular binding substrates (IBSs) of thyroid hormones (e.g., CRYM) ( 66 ). These carriers appear to be necessary components of the feedback control, as simulated for IBS and demonstrated for MCT8 deficiency ( 27 , 65 ).…”

Section: Molecular Mechanisms Involved In the Feedback Controlmentioning

confidence: 99%

“…The recent findings are in agreement with earlier studies in the rat ( 64 , 202 , 203 ). T3 supply is locally controlled by several mechanisms, such as active thyroid hormone uptake, tissue-specific expression and activity of two distinct types of deiodinases converting T3 from T4, and thyroid hormone inactivation by deiodination or degradation by sulfatation, deamination, or glucoronidation ( 57 – 66 ). The regulation varies by tissue as the brain predominantly expresses type 2 deiodinase, whereas type 1 deiodinase is abundant in other tissues of the body, and by thyroid state, as T3 excess upregulates type 1 deiodinase but downregulates type 2 deiodinase, which is upregulated in hypothyroidism ( 57 – 64 ).…”

Section: Homeostatic Considerations In T4-treated Patientsmentioning

confidence: 99%

Homeostatic Control of the Thyroid–Pituitary Axis: Perspectives for Diagnosis and Treatment

et al. 2015

View full text Add to dashboard Cite

The long-held concept of a proportional negative feedback control between the thyroid and pituitary glands requires reconsideration in the light of more recent studies. Homeostatic equilibria depend on dynamic inter-relationships between thyroid hormones and pituitary thyrotropin (TSH). They display a high degree of individuality, thyroid-state-related hierarchy, and adaptive conditionality. Molecular mechanisms involve multiple feedback loops on several levels of organization, different time scales, and varying conditions of their optimum operation, including a proposed feedforward motif. This supports the concept of a dampened response and multistep regulation, making the interactions between TSH, FT4, and FT3 situational and mathematically more complex. As a homeostatically integrated parameter, TSH becomes neither normatively fixed nor a precise marker of euthyroidism. This is exemplified by the therapeutic situation with l-thyroxine (l-T4) where TSH levels defined for optimum health may not apply equivalently during treatment. In particular, an FT3–FT4 dissociation, discernible FT3–TSH disjoint, and conversion inefficiency have been recognized in l-T4-treated athyreotic patients. In addition to regulating T4 production, TSH appears to play an essential role in maintaining T3 homeostasis by directly controlling deiodinase activity. While still allowing for tissue-specific variation, this questions the currently assumed independence of the local T3 supply. Rather it integrates peripheral and central elements into an overarching control system. On l-T4 treatment, altered equilibria have been shown to give rise to lower circulating FT3 concentrations in the presence of normal serum TSH. While data on T3 in tissues are largely lacking in humans, rodent models suggest that the disequilibria may reflect widespread T3 deficiencies at the tissue level in various organs. As a consequence, the use of TSH, valuable though it is in many situations, should be scaled back to a supporting role that is more representative of its conditional interplay with peripheral thyroid hormones. This reopens the debate on the measurement of free thyroid hormones and encourages the identification of suitable biomarkers. Homeostatic principles conjoin all thyroid parameters into an adaptive context, demanding a more flexible interpretation in the accurate diagnosis and treatment of thyroid dysfunction.

show abstract

“…Studies revealed that Crym modulates T3 transportation from the cytoplasm to the nucleus and is involved in the regulation of binding to the thyroid hormone receptor and activation of T3‐responsive genes (32). Indeed, Crym is considered a positive regulator of thyroid hormone action (11). However, Crym ‐KO mice exhibit accelerated T3 and thyroxine (T4) turnover in serum and tissues, but normal growth without alterations in peripheral T3 actions (12).…”

Section: Discussionmentioning

confidence: 99%

“…μ‐Crystallin (Crym) was first identified in the kangaroo eye lens and has been characterized as an NADPH‐dependent cytosolic triiodothyronine (T3)‐binding protein, modulating T3 transportation from cytoplasm to the nucleus (9–11). Crym positively regulates thyroid hormone action by promoting T3 binding to thyroid hormone receptor‐containing dimers, which in turn bind to genomic thyroid‐responsive elements to control the expression of thyroid hormone‐responsive genes in the nucleus.…”

mentioning

confidence: 99%

μ‐Crystallin controls muscle function through thyroid hormone action

Seko¹,

Ogawa²,

Li³

et al. 2015

FASEB j.

View full text Add to dashboard Cite

μ-Crystallin (Crym), a thyroid hormone-binding protein, is abnormally up-regulated in the muscles of patients with facioscapulohumeral muscular dystrophy, a dominantly inherited progressive myopathy. However, the physiologic function of Crym in skeletal muscle remains to be elucidated. In this study, Crym was preferentially expressed in skeletal muscle throughout the body. Crym-knockout mice exhibited a significant hypertrophy of fast-twitch glycolytic type IIb fibers, causing an increase in grip strength and high intensity running ability in Crym-null mice. Genetic inactivation of Crym or blockade of Crym by siRNA-mediated knockdown up-regulated the gene expression of fast-glycolytic contractile fibers in satellite cell-derived myotubes in vitro These alterations in Crym-inactivated muscle were rescued by inhibition of thyroid hormone, even though Crym is a positive regulator of thyroid hormone action in nonmuscle cells. The results demonstrated that Crym is a crucial regulator of muscle plasticity, controlling metabolic and contractile properties of myofibers, and thus the selective inactivation of Crym may be a potential therapeutic target for muscle-wasting diseases, such as muscular dystrophies and age-related sarcopenia.-Seko, D., Ogawa, S., Li, T.-S., Taimura, A., Ono, Y. μ-Crystallin controls muscle function through thyroid hormone action.

show abstract

Cytosolic T3-binding protein modulates dynamic alteration of T3-mediated gene expression in cells

Cited by 14 publications

References 15 publications

Overcoming Monocarboxylate Transporter 8 (MCT8)-Deficiency to Promote Human Oligodendrocyte Differentiation and Myelination

Overcoming Monocarboxylate Transporter 8 (MCT8)-Deficiency to Promote Human Oligodendrocyte Differentiation and Myelination

Homeostatic Control of the Thyroid–Pituitary Axis: Perspectives for Diagnosis and Treatment

μ‐Crystallin controls muscle function through thyroid hormone action

Contact Info

Product

Resources

About