Complex actions of thyroid hormone receptor antagonist NH-3 on gene promoters in different cell lines

Shah, Vanya; Nguyen, Phuong; Nguyen, Ngoc Ha; Togashi, Marie; Scanlan, Thomas S.; Baxter, John D.; Webb, Paul

doi:10.1016/j.mce.2008.09.016

Cited by 16 publications

(13 citation statements)

References 63 publications

(104 reference statements)

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“…28,41−44 An explanation for the biphasic effects of NH3 is its ability to induce some coactivator binding in addition to release of the corepressor NCoR for TR, resulting in TH agonism. 42 Thus, we speculate that TBBPA alone could behave as a weaker TH agonist than T3. When numerous TBBPA molecules coexist with T3, however, TBBPA competes with T3 for TR and results in an inhibitory effect on TH actions.…”

Section: ■ Discussionmentioning

confidence: 86%

Tetrabromobisphenol A Disrupts Vertebrate Development via Thyroid Hormone Signaling Pathway in a Developmental Stage-Dependent Manner

Zhang¹,

Lou³

et al. 2014

Environ. Sci. Technol.

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Data concerning effects of tetrabromobisphenol A (TBBPA) on thyroid hormone (TH)-dependent vertebrate development have been limited, although TBBPA has been demonstrated in vitro to disrupt the TH signaling pathway at the transcriptional level. In this study, we investigated the effects of TBBPA on T3-induced and spontaneous Xenopus laevis metamorphosis, which share many similarities with TH-dependent development in higher vertebrates. In a 6-day T3-induced metamorphosis assay using premetamorphic tadpoles, 10-1000 nM TBBPA exhibited inhibitory effects on T3-induced expression of TH-response genes and morphological changes in a concentration-dependent manner, with a weak stimulatory action on tadpole development and TH-response gene expression in the absence of T3 induction. In a spontaneous metamorphosis assay, we further found that TBBPA promoted tadpole development from stage 51 to 56 (pre- and prometamorphic stages) but inhibited metamorphic development from stage 57 to 66 (metamorphic climax). These results strongly show that TBBPA, even at low concentrations, disrupts TH-dependent development in a developmental stage-dependent manner, i.e., TBBPA exhibits an antagonistic activity at the developmental stages when animals have high endogenous TH levels, whereas it acts as an agonist at the developmental stages when animals have low endogenous TH levels. Our study highlights the adverse influences of TBBPA on TH-dependent development in vertebrates.

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Section: ■ Discussionmentioning

confidence: 86%

Tetrabromobisphenol A Disrupts Vertebrate Development via Thyroid Hormone Signaling Pathway in a Developmental Stage-Dependent Manner

Zhang¹,

Lou³

et al. 2014

Environ. Sci. Technol.

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“…Consistent with effects on gene transcription, NH-3 was more efficacious than SJ-AK in its effects on coregulator binding, when both were applied at concentrations higher than saturating. NH-3 has previously been reported to stimulate transient NCoR recruitment to the growth hormone TRE in GC pituitary cells ( 41 ). Thus both corepressor recruitment and coactivator loss most likely contribute to the action of SJ-AK and NH-3.…”

Section: Resultsmentioning

confidence: 98%

Similarities and Differences between Two Modes of Antagonism of the Thyroid Hormone Receptor

Sadana

Hwang²,

Attia³

et al. 2011

ACS Chem. Biol.

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Thyroid hormone (T3) mediates diverse physiological functions including growth, differentiation, and energy homeostasis through the thyroid hormone receptors (TR). The TR bind DNA at specific recognition sequences in the promoter regions of their target genes known as the thyroid hormone response elements (TREs). Gene expression at TREs regulated by TRs is mediated by coregulator recruitment to the DNA bound receptor. This TR-coregulator interaction controls transcription of target genes by multiple mechanisms including covalent histone modifications and chromatin remodeling. Our previous studies identified a β-aminoketone as a potent inhibitor of the TR-coactivator interaction. We describe here the activity of one of these inhibitors in modulating effects of T3 signaling in comparison to an established ligand-competitive inhibitor of TR, NH-3. The β-aminoketone was found to reverse thyroid hormone induced gene expression by inhibiting coactivator recruitment at target gene promoters, thereby regulating downstream effects of thyroid hormone. While mimicking the downstream effects of a ligand competitive inhibitor at the molecular level, the β-aminoketone affects only a subset of the thyroid responsive signaling network. Thus antagonists directed to the coregulator binding site have distinct pharmacological properties relative to ligand based antagonists and may provide complementary activity in vivo.

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“…Several factors may contribute to this response, i.e. unliganded TRs have ligand-independent actions; thus, unligandedor 1-850-liganded TRs may adopt altered conformations, which could change coregulator recruitment and specific gene expression independently of the effects on TH binding (Shah et al 2008). Nonetheless, in all cases, the effects of 1-850 were blunted after treatment with T 3 or T 2 .…”

Section: Discussionmentioning

confidence: 98%

3,5-di-iodothyronine stimulates tilapia growth through an alternate isoform of thyroid hormone receptor β1

Navarrete‐Ramírez¹,

Luna²,

Valverde-R³

et al. 2013

Journal of Molecular Endocrinology

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Recent studies in our laboratory have shown that in some teleosts, 3,5-di-iodothyronine (T 2 or 3,5-T 2 ) is as bioactive as 3,5,3 0 -tri-iodothyronine (T 3 ) and that its effects are in part mediated by a TRb1 (THRB) isoform that contains a 9-amino acid insert in its ligand-binding domain (long TRb1 (L-TRb1)), whereas T 3 binds preferentially to a short TRb1 (S-TRb1) isoform that lacks this insert. To further understand the functional relevance of T 2 bioactivity and its mechanism of action, we used in vivo and ex vivo (organotypic liver cultures) approaches and analyzed whether T 3 and T 2 differentially regulate the S-TRb1 and L-TRb1s during a physiological demand such as growth. In vivo, T 3 and T 2 treatment induced body weight gain in tilapia. The expression of L-TRb1 and S-TRb1 was specifically regulated by T 2 and T 3 respectively both in vivo and ex vivo. The TR antagonist 1-850 effectively blocked thyroid hormone-dependent gene expression; however, T 3 or T 2 reversed 1-850 effects only on S-TRb1 or L-TRb1 expression, respectively. Together, our results support the notion that both T 3 and T 2 participate in the growth process; however, their effects are mediated by different, specific TRb1 isoforms.

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Complex actions of thyroid hormone receptor antagonist NH-3 on gene promoters in different cell lines

Cited by 16 publications

References 63 publications

Tetrabromobisphenol A Disrupts Vertebrate Development via Thyroid Hormone Signaling Pathway in a Developmental Stage-Dependent Manner

Tetrabromobisphenol A Disrupts Vertebrate Development via Thyroid Hormone Signaling Pathway in a Developmental Stage-Dependent Manner

Similarities and Differences between Two Modes of Antagonism of the Thyroid Hormone Receptor

3,5-di-iodothyronine stimulates tilapia growth through an alternate isoform of thyroid hormone receptor β1

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