Interaction of human beta 1 thyroid hormone receptor and its mutants with DNA and retinoid X receptor beta. T3 response element-dependent dominant negative potency.

Meier, Christoph A.; Parkison, Clifford; Chen, A; Ashizawa, Kiyoto; Meier-Heusler, S C; Muchmore, P; Cheng, Sheue-yann; Weintraub, Bruce D.

doi:10.1172/jci116793

Cited by 77 publications

(38 citation statements)

References 38 publications

(34 reference statements)

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“…The ability of the mutant proteins to bind ligand is moderately or severely impaired (Table II). Other studies have shown that mutant receptors retain the ability to bind to DNA (27)(28)(29) either as homodimers (42) or heterodimers with the retinoid X receptor (30). These functional properties correlate with the observation that RTH mutations lie outside the DNA-binding domain and highly conserved motifs (43)(44)(45) that are known to be involved in dimerization.…”

Section: Discussionmentioning

confidence: 87%

“…We and others (27,28) have also shown that the mutant receptor proteins inhibitwild-type receptor action in a dominant negative manner. Importantly, this inhibition has been observed with reporter genes containing not only positive TREs (29)(30)(31), but also the human TSHa promoter (15,28,46), which is negatively regulated by hTR/3. A number of models have been proposed to account for dominant negative inhibition (28,42), but recent studies indicate that artificial mutations that abolish DNA binding or heterodimerization with RXR are able to abrogate dominant negative inhibitory effects with reporter genes containing the hTSHa promoter or positive TREs (47,48).…”

Section: Discussionmentioning

confidence: 93%

“…In addition, they are able to inhibit the action of wild-type receptor when coexpressed (27,28). This dominant negative inhibitory activity varies depending on the nature of the mutation (29), as well as the configuration of TRE (30,31 ). Evidence in favor of the dominant negative effect of mutant receptors in vivo is provided by the observation that individuals who are heterozygous for a complete deletion of one hTR,3 allele are normal (12), whereas an individual who was homozygous for a dominant negative receptor mutation showed severe resistance (32).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene.

Adams¹,

Matthews²,

Collingwood³

et al. 1994

J. Clin. Invest.

217

108

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene.

Adams¹,

Matthews²,

Collingwood³

et al. 1994

J. Clin. Invest.

217

108

View full text Add to dashboard Cite

show abstract

“…In vitro-translated TR␤1 and/or Ear-2 was incubated with the labeled oligonucleotides in binding buffer (18,21) in the presence or absence of antibody. For TR␤1, anti-TR␤1 MAb C4 (36) was used; for Ear-2, PC-9 was used.…”

Section: Methodsmentioning

confidence: 99%

The Orphan Nuclear Receptor Ear-2 Is a Negative Coregulator for Thyroid Hormone Nuclear Receptor Function

Zhu

Park

Kaneshige

et al. 2000

Molecular and Cellular Biology

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Thyroid hormone (T3) nuclear receptors (TR) are ligand-dependent transcription factors which regulate growth, differentiation, and development. One emerging hypothesis suggests that TR mediate these diverse effects via a large network of coregulators. Recently, we found that TR-mediated transcriptional responses varied in six cell lines derived from different tissues. We therefore used human TR subtype ␤1 (TR␤1) as bait to search for coregulators in human colon carcinoma RKO cells with a yeast two-hybrid system. RKO cells exhibited T3-dependent and -independent transcriptional activation. One of the three positive clones was identified as Ear-2, which is a distant member of the chick ovalbumin upstream promoter-transcription factors of the orphan nuclear receptor family. The physical interaction between Ear-2 and TR␤1 was further confirmed by specific binding of Ear-2 to glutathione S-transferase-TR␤1. In addition, Ear-2 was found to associate with TR␤1 in cells. As a result of this physical interaction, binding of TR␤1 to the T3 response elements was inhibited. Using reporter systems, we found that both the basal activation and the T3-dependent activation mediated by TR␤1 were repressed by Ear-2 in CV1 cells. In RKO cells, however, the T3-independent transcriptional activity was more sensitive to the repression effect of Ear-2 than the T3-dependent transcriptional activity. The repression effect of Ear-2 was reversed by steroid hormone receptor coactivator 1. These results suggest that TR-mediated responses reflect a balance of corepressors and coactivators in cells. These findings further strengthen the hypothesis that the diverse activities of TR are achieved via a large network of coregulators that includes Ear-2.Thyroid hormone, 3,3Ј,5-triiodo-L-thyronine (T3), is important for the growth, development, and differentiation of vertebrates. It is also essential for maintaining metabolic-energetic homeostasis. These biological activities of T3 are mediated by T3 nuclear receptors (TR), which are members of the steroid hormone and retinoic acid receptor superfamily (28). Like other nuclear receptors, TR consists of modular domains which include the amino-terminal A/B domain, the central DNA binding domain (domain C), and the hormone binding domains (domains D and E). Two TR genes, ␣ and ␤, located on chromosomes 17 and 3, respectively, give rise to receptor isoforms (␣1, ␣2, ␤1, and ␤2) by alternative splicing. TR mediates the action of T3 by binding to the cis elements on the promoter regions of target genes. TR binds to specific sequences known as T3 response elements (TRE), containing the consensus AGGTCA half-site binding motifs arranged in an inverted repeat, everted repeat, or direct repeat separated by 4 nucleotides (DR4) (4). The transcriptional activity of TR depends not only on the types of TRE but also on T3. In the absence of T3, TR acts as a repressor. Binding of T3 leads TR to function as a transcriptional activator (11).While the mechanism(s) underlying the repression and activation functions of T...

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“…The T7 expression plasmids used for in vitro transcription/translation were pCJ3 (TRβ1), pJL08 (ED41), pJL06 (MD32), pCJ4 (KD25), pCJ7 (KP24), and pGEM-PV (PV), which have been previously described (6,33,34).…”

Section: Methodsmentioning

confidence: 99%

Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone β receptor inhibits mitotic progression

Ying¹,

Furuya²,

Zhao³

et al. 2006

J. Clin. Invest.

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Overexpression of pituitary tumor-transforming 1 (PTTG1) is associated with thyroid cancer. We found elevated PTTG1 levels in the thyroid tumors of a mouse model of follicular thyroid carcinoma (TRβ PV/PV mice). Here we examined the molecular mechanisms underlying elevated PTTG1 levels and the contribution of increased PTTG1 to thyroid carcinogenesis. We showed that PTTG1 was physically associated with thyroid hormone β receptor (TRβ) as well as its mutant, designated PV. Concomitant with thyroid hormone-induced (T3-induced) degradation of TRβ, PTTG1 proteins were degraded by the proteasomal machinery, but no such degradation occurred when PTTG1 was associated with PV. The degradation of PTTG1/TRβ was activated by the direct interaction of the liganded TRβ with steroid receptor coactivator 3 (SRC-3), which recruits proteasome activator PA28γ. PV, which does not bind T3, could not interact directly with SRC-3/PA28γ to activate proteasome degradation, resulting in elevated PTTG1 levels. The accumulated PTTG1 impeded mitotic progression in cells expressing PV. Our results unveil what we believe to be a novel mechanism by which PTTG1, an oncogene, is regulated by the liganded TRβ. The loss of this regulatory function in PV led to an aberrant accumulation of PTTG1 disrupting mitotic progression that could contribute to thyroid carcinogenesis. IntroductionFollicular and papillary thyroid carcinomas are the most common thyroid malignancies. Although both are well-differentiated cancers, each has distinguishable morphological and pathological characteristics (1). Follicular thyroid carcinoma has a greater tendency than does papillary cancer to metastasize to distant sites. Such distant metastasis predicts a poor response to treatment and subsequent progression and mortality from thyroid cancer. Despite recent progress in the identification of key genetic alterations and aberrant molecular pathways, the precise mechanisms underlying the initiation and progression of follicular thyroid cancer are not fully understood.The development of a mouse model of follicular thyroid cancer (TRβ PV/PV mice) has provided a valuable tool to elucidate the molecular basis underlying thyroid carcinogenesis (2). The TRβ PV/PV mouse was created by a targeted mutation of thyroid hormone β receptor (TRβ) via homologous recombination and the Cre-LoxP system (3). The TRβ mutant (referred to here as PV) was identified in a patient with resistance to thyroid hormone (RTH) (4). RTH is caused by mutations of the TRβ gene and manifests symptoms as a result of decreased sensitivity to

show abstract

Interaction of human beta 1 thyroid hormone receptor and its mutants with DNA and retinoid X receptor beta. T3 response element-dependent dominant negative potency.

Abstract: Mutations in the human beta thyroid hormone receptor (h-TRB)

Cited by 77 publications

References 38 publications

Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene.

Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene.

The Orphan Nuclear Receptor Ear-2 Is a Negative Coregulator for Thyroid Hormone Nuclear Receptor Function

Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone β receptor inhibits mitotic progression

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