Nomenclature of thyroid hormone receptor beta-gene mutations in resistance to thyroid hormone: consensus statement from the first workshop on thyroid hormone resistance, July 10-11, 1993, Cambridge, United Kingdom.

Beck‐Peccoz, Paolo; Chatterjee, Krishna; Chin, W. W.; DeGroot, Leslie J.; Jameson, J. Larry; Nakamura, Hirotoshi; Refetoff, Samuel; Usala, Stephen J.; Weintraub, B

doi:10.1210/jcem.78.4.8157732

Cited by 25 publications

(11 citation statements)

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“…Thus, ␤3 (K D ϭ 0.63 Ϯ 0.13 nM) and ⌬␤3 (K D ϭ 0.51 Ϯ 0.09 nM) bound T 3 with high affinity, similar to ␤1 (K D ϭ 0.49 Ϯ 0.10 nM) and in agreement with published data (28). E. coli extracts transformed with empty vector did not bind T 3 .…”

Section: Fig 4 (A) Multiple-tissuesupporting

confidence: 91%

“…Repression of ␤1-mediated induction of each TRE by ⌬␤3 was proportional to the concentration of cotransfected ⌬␤3 (Fig. 9B) and correlated with the degree to which the three elements were activated by T 3 . Antagonism of ␤3 actions by ⌬␤3 differed between the TREs and, in contrast, involved an initial potentiation of TR␤3 action on the MHC and PAL elements (Fig.…”

Section: Discussionmentioning

confidence: 88%

“…Two T 3 receptor (TR) genes, TR␣ (NR1A1) and TR␤(NR1A2), are conserved in vertebrates (32,43), while two TR␣ and two TR␤ genes have arisen by gene duplication in Xenopus laevis (65). TR␣ encodes three C-terminal variants in mammals: ␣1 (NR1A1a) binds T 3 and DNA and is a functional receptor, whereas ␣2 (NR1A1b) and ␣3 (NR1A1c) do not bind T 3 and are weak dominant negative antagonists in vitro, although their roles in vivo are unclear (33,40,50,57). Recent studies have described a promoter in intron 7 of TR␣, which generates two truncated variants, ⌬␣1 and ⌬␣2, that are repressors in vitro but are of unknown physiological significance (9).…”

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Cloning and Characterization of Two Novel Thyroid Hormone Receptor β Isoforms

Williams

2000

Molecular and Cellular Biology

257

166

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Thyroid hormone (T 3 ) activates nuclear receptor transcription factors, encoded by the TR␣ (NR1A1) and TR␤ (NR1A2) genes, to regulate target gene expression. Several TR isoforms exist, and studies of null mice have identified some unique functions for individual TR variants, although considerable redundancy occurs, raising questions about the specificity of T 3 action. Thus, it is not known how diverse T 3 actions are regulated in target tissues that express multiple receptor variants. I have identified two novel TR␤ isoforms that are expressed widely and result from alternative mRNA splicing. TR␤3 is a 44.6-kDa protein that contains an unique 23-amino-acid N terminus and acts as a functional receptor. TR⌬␤3 is a 32.8-kDa protein that lacks a DNA binding domain but retains ligand binding activity and is a potent dominant-negative antagonist. The relative concentrations of ␤3 and ⌬␤3 mRNAs vary between tissues and with changes in thyroid status, indicating that alternative splicing is tissue specific and T 3 regulated. These data provide novel insights into the mechanisms of T 3 action and define a new level of specificity that may regulate thyroid status in tissue.The actions of thyroid hormone, 3,5,3Ј-L-triiodothyronine (T 3 ), are mediated by ligand-inducible transcription factors that are members of the steroid/thyroid hormone receptor superfamily. Two T 3 receptor (TR) genes, TR␣ (NR1A1) and TR␤(NR1A2), are conserved in vertebrates (32, 43), while two TR␣ and two TR␤ genes have arisen by gene duplication in Xenopus laevis (65). TR␣ encodes three C-terminal variants in mammals: ␣1 (NR1A1a) binds T 3 and DNA and is a functional receptor, whereas ␣2 (NR1A1b) and ␣3 (NR1A1c) do not bind T 3 and are weak dominant negative antagonists in vitro, although their roles in vivo are unclear (33,40,50,57). Recent studies have described a promoter in intron 7 of TR␣, which generates two truncated variants, ⌬␣1 and ⌬␣2, that are repressors in vitro but are of unknown physiological significance (9). In contrast, TR␤ encodes two N-terminal variants, ␤1 (NR1A2a) and ␤2 (NR1A2b), which are transcribed from separate promoters (24,28,42,61). The ␤1 N terminus is encoded by two exons that are replaced by a single exon in ␤2. These exons are alternatively spliced to six common exons that encode the DNA binding, ligand binding, and dimerization domains of the receptor (32). This arrangement is conserved in vertebrates, and the invariant splice site between the divergent N termini and the first of the common exons is known as the changing point (65). The changing point is retained in both Xenopus TR␤ genes, although additional splicing in the 5Ј untranslated region (5Ј-UTR) results in many transcripts that are temporo-spatially restricted during development (51, 64). TR␤0 is expressed in chicken; it contains only 2 amino acids proximal to the changing point and is similar to a short TR␤ in Xenopus, although a mammalian homologue has not been identified (18,52,65). T 3 -regulated development in chicken also involves temporospatially...

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Section: Fig 4 (A) Multiple-tissuesupporting

confidence: 91%

Section: Discussionmentioning

confidence: 88%

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confidence: 99%

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Cloning and Characterization of Two Novel Thyroid Hormone Receptor β Isoforms

Williams

2000

Molecular and Cellular Biology

257

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“…The plasmid pCMX-NCoR was provided by M. G. Rosenfeld (25). The numbering of the amino acid residues of TR␤ is based on a consensus nomenclature (4).…”

Section: Methodsmentioning

confidence: 99%

Nuclear Receptor Corepressors Activate Rather than Suppress Basal Transcription of Genes That Are Negatively Regulated by Thyroid Hormone

Tagami

Madison

Nagaya

et al. 1997

Molecular and Cellular Biology

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186

118

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A group of transcriptional cofactors referred to as corepressors (CoRs) were recently shown to play a central role in basal silencing of genes that contain positive triiodothyronine (T3) response elements. In a reciprocal manner, negatively regulated genes are stimulated by unliganded thyroid hormone receptor (TR) and repressed upon the addition of T3. We used a TR␤ mutant, called P214R, which fails to interact with CoRs, to examine whether CoRs also play a role in the control of genes that are negatively regulated in response to T3. In studies of three negatively regulated genes (the pituitary thyroid-stimulating hormone ␣-subunit [TSH␣], TSH␤, and hypothalamic thyrotropin-releasing hormone [TRH] genes), stimulation of basal promoter activity by unliganded TR␤ was impaired by introducing the P214R CoR mutation. Coexpression of each of the CoRs SMRT (silencing mediator for retinoid receptors and TRs) and NCoR (nuclear receptor CoR) enhanced basal stimulation of the negatively regulated promoters in a TR-dependent manner, but this effect was not seen with the P214R TR mutant. The mechanism of CoR effects on negatively regulated promoters was explored further with a series of GAL4-TR chimeric receptors and mutants that allowed TR effects to be assessed independently of receptor interactions with DNA. These experiments revealed that, like the negative regulation of genes by wild-type TR, basal activation occurred with GAL4-TR, but not with the GAL4-P214R mutant, and was reversed by the addition of T3. These results suggest that TR interactions with negatively regulated genes may be driven through protein-protein interactions. We conclude that a subset of negatively regulated genes are controlled by a novel mechanism that involves TR-mediated recruitment and basal activation by SMRT and NCoR. Addition of T3 reverses basal activation, perhaps by dissociation of CoRs.Thyroid hormone receptors (TRs) function as transcription factors to increase or decrease levels of gene expression. In the unliganded state, TRs and retinoic acid receptors can suppress or silence the basal activity of promoters that contain positively regulated hormone response elements (2, 6, 12). The addition of ligand reverses gene silencing and induces strong stimulation of these genes. Recently, nuclear corepressors (CoRs), termed NCoR (nuclear receptor CoR) (22, 25) and SMRT (silencing mediator for retinoid receptors and TRs) (9), were identified and were shown to mediate ligand-independent repression. The CoRs interact with the ligand binding domain (LBD) of nuclear receptors, and several mutations in the CoR box at the amino-terminal end of the LBD have been shown to disrupt interactions with CoRs (9, 22, 25).Although most research in the thyroid hormone action field has involved pathways of positive regulation by triiodothyronine (T3), it has been estimated that nearly equal numbers of genes are repressed in response to T3 in vivo (34). However, the molecular mechanisms responsible for TR-mediated negative regulation remain poorly defined. It i...

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“…The numbering of the amino acid residues of TRb is based on a consensus nomenclature (Beck-Peccoz et al 1994). Mutant and WT receptor cDNAs were subcloned into pCMX (Umesono et al 1991) and pCMX-VP16 (Tagami et al 1999) for in vitro transcription/translation and for transient expression in transfected cells.…”

Section: Plasmid Constructionsmentioning

confidence: 99%

The retinoid X receptor binding to the thyroid hormone receptor: relationship with cofactor binding and transcriptional activity

Tagami

Yamamoto²,

Moriyama³

et al. 2009

Journal of Molecular Endocrinology

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Transcriptional regulation is mediated by thyroid hormone (tri-iodothyronine, T 3 ) receptors (TR), which bind to T 3 response elements as heterodimers with retinoid X receptors (RXR). TR binds to corepressor proteins (CoR) in the absence of T 3 , which mediate transcriptional repression and to coactivator proteins (CoA) in the presence of T 3 , which mediate transcriptional stimulation, by recruiting additional proteins to the promoter. To determine the relationship between TR functions and cofactor bindings, we selected 13 single-point mutants on the ligand binding domain of TR, of which T 3 bindings were well preserved and created VP16 chimeric receptors.

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Nomenclature of thyroid hormone receptor beta-gene mutations in resistance to thyroid hormone: consensus statement from the first workshop on thyroid hormone resistance, July 10-11, 1993, Cambridge, United Kingdom.

Cited by 25 publications

References 0 publications

Cloning and Characterization of Two Novel Thyroid Hormone Receptor β Isoforms

Cloning and Characterization of Two Novel Thyroid Hormone Receptor β Isoforms

Nuclear Receptor Corepressors Activate Rather than Suppress Basal Transcription of Genes That Are Negatively Regulated by Thyroid Hormone

The retinoid X receptor binding to the thyroid hormone receptor: relationship with cofactor binding and transcriptional activity

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