Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

Shibusawa, Nobuyuki; Hollenberg, Anthony N.; Wondisford, Fredric E.

doi:10.1074/jbc.m207264200

Cited by 117 publications

(87 citation statements)

References 59 publications

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“…5). Gal4-NCoR, Gal4-SRC (LXXLL), and Gal4-SRC (q-rich) are able to bind to TR as expected (Christiaens et al 2002, Shibusawa et al 2003a, Iwasaki et al 2006) and this interaction is independent of an intact DBD of TR (Fig. 4B).…”

Section: Discussionmentioning

confidence: 66%

“…4, all Gal4-cofactor fusion proteins were able to bind TR in a ligand-dependent manner. NCoR binds TR in the absence of T 3 whereas the SRC-1 binds TR in the presence of T 3 , as expected (Shibusawa et al 2003a). This binding is unaffected by point mutations within the DBD of TR, although the fold-repression ratesGT 3 are reduced compared with wild-type TR (Fig.…”

Section: Resultsmentioning

confidence: 76%

“…Furthermore, introduction of point mutations within the DBD of TRb, which prevents binding to TRE (GS mutant) conserved some but not all phenotypical alterations in mice compared with conventional TRb knockout animals (Shibusawa et al 2003b). Since the overall structure of this DBD mutant remains unaffected (Shibusawa et al 2003a), it is likely that a suggested protein-protein interaction domain remains intact. As also suggested for different members of the nuclear receptor family, these proteins are targets of post-translational modifications, which facilitate their function within the transrepression mechanism (Moeller et al 2005, Hiroi et al 2006, Kenessey & Ojamaa 2006, Storey et al 2006, Wulf et al 2007.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the functional readout on a negative TRE is diametrically opposed to the readout on a positive TRE. DNA sequences close to the transcriptional start site (the so-called z-boxes) have been suggested to be the binding sites for TR within the TRH, thyroid-stimulating hormone b (TSHb), and necdin gene promoters (Sasaki et al 1999, Satoh et al 1999, Shibusawa et al 2003a, Nygard et al 2006. In a second model, TR inhibits the function of another DNA-binding protein in a liganddependent manner.…”

Section: Introductionmentioning

confidence: 99%

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The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription

Wulf¹,

Wetzel²,

Kebenko³

et al. 2008

Journal of Molecular Endocrinology

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Thyroid hormone 3,3 0 ,5-tri-iodothyronine (T 3 ) regulates gene expression in a positive and negative manner. Here, we analyzed the regulation of a positively (mitochondrial glycerol-3-phosphate dehydrogenase) and negatively T 3 -regulated target gene (TSHa). Thyroid hormone receptor (TR) activates mGPDH but not TSH promoter fragments in a mammalian one-hybrid assay. Furthermore, we investigated functional consequences of targeting TR to DNA independent of its own DNA-binding domain (DBD). Using a chimeric fusion protein of the DBD of yeast transcription factor Gal4 with TR, we demonstrated a positive regulation of gene transcription in response to T 3 . T 3 -mediated activation of this chimeric protein is further increased after an introduction of point mutations within the DBD of TR. Moreover, we investigated the capacity of TR to negatively regulate gene transcription on a DNA-tethered cofactor platform. A direct binding of TR to DNA via its own DBD is dispensable in this assay. We investigated functional consequences of point mutations affecting different domains of TR. Our data indicate that the DBD of TR plays a key role in direct DNA binding on positively but not on negatively T 3 -regulated target genes. Nevertheless, the DBD is involved in mediating negative gene regulation independent of its capacity to bind DNA.

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Section: Discussionmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription

Wulf¹,

Wetzel²,

Kebenko³

et al. 2008

Journal of Molecular Endocrinology

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“…S7A). In addition, we demonstrated that TET3 stabilized and promoted chromatin association of a TRα1 mutant (TRα1 G75S ) defective in DNA binding (15) as a result of a mutation in DNA binding domain (Fig. S7B).…”

Section: Discussionmentioning

confidence: 90%

Methylcytosine dioxygenase TET3 interacts with thyroid hormone nuclear receptors and stabilizes their association to chromatin

Guan

Guyot

Samarut

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily that act as ligand-dependent transcription factors. Here we identified the ten-eleven translocation protein 3 (TET3) as a TR interacting protein increasing cell sensitivity to T3. The interaction between TET3 and TRs is independent of TET3 catalytic activity and specifically allows the stabilization of TRs on chromatin. We provide evidence that TET3 is required for TR stability, efficient binding of target genes, and transcriptional activation. Interestingly, the differential ability of different TRα1 mutants to interact with TET3 might explain their differential dominant activity in patients carrying TR germline mutations. So this study evidences a mode of action for TET3 as a nonclassical coregulator of TRs, modulating its stability and access to chromatin, rather than its intrinsic transcriptional activity. This regulatory function might be more general toward nuclear receptors. Indeed, TET3 interacts with different members of the superfamily and also enhances their association to chromatin.thyroid hormone receptor | methylcytosine dioxygenase TET3 | protein stability | chromatin recruitment | RTH syndrome T hyroid hormone (T3) is the main natural iodinated compound possessing a biological activity. It exerts a pleiotropic action on development and homeostasis, acting on most, if not all, cell types (1). T3 acts directly on gene transcription by binding to the thyroid hormone receptors (TRs) TRα1, TRβ1, and TRβ2. They are, respectively, encoded by the THRA and THRB genes. In humans, mutations of either THRA or THRB cause the resistance to thyroid hormone syndrome (RTH). The severity of the disease is determined by the precise location of the mutation (2), dictating the ability of the mutated TR to respond to T3 (3).TRs, as the other members of the nuclear receptor superfamily, are ligand-regulated transcription factors consisting of three major functional domains: the amino-terminal A/B domain, the DNAbinding domain, and the ligand-binding domain. TRs can bind to DNA on a TR response element (TRE) the in absence of T3, and on most genes they repress transcription until T3 binds and leads to activation. Helix12 is the major structural element associated with this process. T3 triggers a dramatic shift of its position, leading to dissociation of corepressors and recruitment of coactivators, including coactivators that have the ability to change the chromatin microenvironment (4). T3 binding also induces a rapid proteasomemediated degradation of TRs that is associated with T3-dependent transcriptional activity (5). TR availability and chromatin access are thus possibly important levels of modulation of T3 cellular response.The goal of the present study was to identify epigenetic regulators that interact with, and therefore may modulate, TR transcriptional activity, using in vitro pull-down screening. This approach allowed us to identify TET3, a member of the ten-eleven translocation (TET) family proteins, as a partner for TRs....

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Hypothalamus‐Pituitary‐Thyroid Axis

Ortiga-Carvalho

Chiamolera

Pazos‐Moura

et al. 2016

Comprehensive Physiology

336

222

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The hypothalamus-pituitary-thyroid (HPT) axis determines the set point of thyroid hormone (TH) production. Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the synthesis and secretion of pituitary thyrotropin (thyroid-stimulating hormone, TSH), which acts at the thyroid to stimulate all steps of TH biosynthesis and secretion. The THs thyroxine (T4) and triiodothyronine (T3) control the secretion of TRH and TSH by negative feedback to maintain physiological levels of the main hormones of the HPT axis. Reduction of circulating TH levels due to primary thyroid failure results in increased TRH and TSH production, whereas the opposite occurs when circulating THs are in excess. Other neural, humoral, and local factors modulate the HPT axis and, in specific situations, determine alterations in the physiological function of the axis. The roles of THs are vital to nervous system development, linear growth, energetic metabolism, and thermogenesis. THs also regulate the hepatic metabolism of nutrients, fluid balance and the cardiovascular system. In cells, TH actions are mediated mainly by nuclear TH receptors (210), which modify gene expression. T3 is the preferred ligand of THR, whereas T4, the serum concentration of which is 100-fold higher than that of T3, undergoes extra-thyroidal conversion to T3. This conversion is catalyzed by 5'-deiodinases (D1 and D2), which are TH-activating enzymes. T4 can also be inactivated by conversion to reverse T3, which has very low affinity for THR, by 5-deiodinase (D3). The regulation of deiodinases, particularly D2, and TH transporters at the cell membrane control T3 availability, which is fundamental for TH action. © 2016 American Physiological Society. Compr Physiol 6:1387-1428, 2016.

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Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

Cited by 117 publications

References 59 publications

The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription

The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription

Methylcytosine dioxygenase TET3 interacts with thyroid hormone nuclear receptors and stabilizes their association to chromatin

Hypothalamus‐Pituitary‐Thyroid Axis

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