Determination of Nuclear Receptor Corepressor Interactions with the Thyroid Hormone Receptor

Makowski, Anita; Brzostek, Sabrina; Cohen, Ronald N.; Hollenberg, Anthony N.

doi:10.1210/me.2002-0310

Cited by 73 publications

(70 citation statements)

References 37 publications

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“…Others have reported that the R429Q mutant TR is impaired for silencing mediator of retinoid and thyroid receptors (SMRT) release in vitro (42), a functional property that has recently been reported in conjunction with deficient NCoR binding in another TR-␤ mutant (Mkar) discovered in a patient with predominantly central RTH (43). However, it is unlikely that the observed specific defect in TH negative regulation with the R429Q mutant is due to defective SMRT release, given that (i) NCoR is the corepressor preferentially recruited by TR-␤ (44,45), (ii) we were unable to detect R429Q TR binding to SMRT in EMSA (data not shown), and (iii) Mkar had defective TH function on both positive and negative TH response elements.…”

Section: Discussionmentioning

confidence: 99%

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Machado

Sabet

Santiago

et al. 2009

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

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Resistance to thyroid hormone (RTH) is most often due to point mutations in the ␤-isoform of the thyroid hormone (TH) receptor (TR-␤). The majority of mutations involve the ligand-binding domain, where they block TH binding and receptor function on both stimulatory and inhibitory TH response elements. In contrast, a few mutations in the ligand-binding domain are reported to maintain TH binding and yet cause RTH in certain tissues. We introduced one such naturally occurring human RTH mutation (R429Q) into the germline of mice at the TR-␤ locus. R429Q knock-in (KI) mice demonstrated elevated serum TH and inappropriately normal thyroid-stimulating hormone (TSH) levels, consistent with hypothalamic-pituitary RTH. In contrast, 3 hepatic genes positively regulated by TH (Dio1, Gpd1, and Thrsp) were increased in R429Q KI animals. Mice were then rendered hypothyroid, followed by graded T 3 replacement. Hypothyroid R429Q KI mice displayed elevated TSH subunit mRNA levels, and T 3 treatment failed to normally suppress these levels. T3 treatment, however, stimulated pituitary Gh levels to a greater degree in R429Q KI than in control mice. Gsta, a hepatic gene negatively regulated by TH, was not suppressed in R429Q KI mice after T 3 treatment, but hepatic Dio1 and Thrsp mRNA levels increased in response to TH. Cardiac myosin heavy chain isoform gene expression also showed a specific defect in TH inhibition. In summary, the R429Q mutation is associated with selective impairment of TH-mediated gene repression, suggesting that the affected domain, necessary for TR homodimerization and corepressor binding, has a critical role in negative gene regulation by TH.corepressor ͉ homodimer ͉ negative regulation ͉ resistance to thyroid hormone T hyroid-stimulating hormone (thyrotropin or TSH) is a heterodimeric glycoprotein consisting of 2 non-covalently linked protein subunits (TSH-␣ and TSH-␤), synthesized in the pituitary thyrotroph, which regulates the thyroid. TSH-releasing hormone (TRH) is synthesized in the paraventricular nucleus of the hypothalamus and released into the portal circulation, where it regulates the synthesis and glycosylation pattern (bioactivity) of pituitary TSH. The hypothalamic-pituitary-thyroid (HPT) axis is regulated by negative feedback involving thyroid hormones (THs) (T 4 and T 3 ), which are produced by the thyroid gland. The major negative regulator of TSH secretion is T 3 , which directly inhibits the transcription of the TSH-␣ and -␤ subunit genes (1-5) and TRH (6-8).TH action is mediated by different isoforms of the TH receptor (TR), which are members of the nuclear receptor superfamily of ligand-modulated transcription factors. Two genes, by alternative splicing and transcriptional start site utilization, express the known ligand-binding TR isoforms, TR-␣1, TR-␤1, TR-␤2, and TR-␤3. Negative regulation of the HPT axis is principally mediated by the ␤ isoform of the TR (9-13).On genes with a positive TH response element, TR interacts with corepressor proteins (CoRs) in the absence of ligand, and this...

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Section: Discussionmentioning

confidence: 99%

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Machado

Sabet

Santiago

et al. 2009

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

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“…Exogenous TH could overcome this inhibition if it induced dissociation of receptor heterodimers prematurely, before the gradient of thyroid hormone becomes established. Thyroid hormone receptors mediate repression (usually in the absence of ligand) by interacting with nuclear co-repressors NCoR and/or SMRT (Eckey et al, 2003;Makowski et al, 2003;Havis et al, 2006). In fact, a growing body of evidence indicates that heterodimers of thyroid hormone and Rxr receptors adopt different configurations based on information provided by the DNA binding site with which they associate, that facilitate or block interactions with co-activators or co-repressors [ (Harvey et al, 2007) and references cited therein; (Ghosh et al, 2002;Diallo et al, 2007)].…”

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confidence: 99%

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

2008

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Rod and cone photoreceptors in the mammalian retina are special types of neurons that are responsible for phototransduction, the first step of vision. Development and maintenance of photoreceptors require precisely regulated gene expression. This regulation is mediated by a network of photoreceptor transcription factors centered on Crx, an Otx-like homeodomain transcription factor. The cell type (subtype) specificity of this network is governed by factors that are preferentially expressed by rods or cones or both, including the rod-determining factors neural retina leucine zipper protein (Nrl) and the orphan nuclear receptor Nr2e3; and cone-determining factors, mostly nuclear receptor family members. The best-documented of these include thyroid hormone receptor β2 (Trβ2), retinoid related orphan receptor Rorβ, and retinoid X receptor Rxrγ. The appropriate function of this network also depends on general transcription factors and co-factors that are ubiquitously expressed, such as the Sp zinc finger transcription factors and STAGA coactivator complexes. These cell type-specific and general transcription regulators form complex interactomes; mutations that interfere with any of the interactions can cause photoreceptor development defects or degeneration. In this manuscript, we review recent progress on the roles of various photoreceptor transcription factors and interactions in photoreceptor subtype development. We also provide evidence of auto-, para-, and feedback regulation among these factors at the transcriptional level. These protein-protein and protein-promoter interactions provide precision and specificity in controlling photoreceptor subtype-specific gene expression, development and survival. Understanding these interactions may provide insights to more effective therapeutic interventions for photoreceptor diseases.

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“…Despite their similarity the RIDs do not function equivalently. TR has been shown to preferably bind NCoR both in vitro and in mammalian cell lines (22,23) via the most 5Ј of its RIDs, N3, which is required for strong interactions with DNA-bound TR (18,21,24). Importantly, N3 must cooperate with another RID, preferably N2, to interact with a TR homodimer on DNA as each TR binds to 1 of the RIDs (18,(21)(22)(23)(24)(25).…”

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confidence: 99%

The nuclear corepressor, NCoR, regulates thyroid hormone action in vivo

Astapova

Lee

Morales

et al. 2008

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

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The thyroid hormone receptor (TR) has been proposed to regulate expression of target genes in the absence of triiodothyronine (T3) through the recruitment of the corepressors, NCoR and SMRT. Thus, NCoR and SMRT may play an essential role in thyroid hormone action, although this has never been tested in vivo. To accomplish this, we developed mice that express in the liver a mutant NCoR protein (L-NCoR⌬ID) that cannot interact with the TR. L-NCoR⌬ID mice appear grossly normal, however, when made hypothyroid the repression of many positively regulated T 3-target genes is abrogated, demonstrating that NCoR plays a specific and sufficient role in repression by TR in the absence of T 3. Remarkably, in the euthyroid state, expression of many T 3-targets is also up-regulated in L-NCoR⌬ID mice, demonstrating that NCoR also determines the magnitude of the response to T 3 in euthyroid animals. Although positive T 3 targets were up-regulated in L-NCoR⌬ID mice in the hypo-and euthyroid state, there was little effect seen on negatively regulated T 3 target genes. Thus, NCoR is a specific regulator of T 3-action in vivo and mediates repression by the unliganded TR in hypothyroidism. Furthermore, NCoR appears to play a key role in determining the tissue-specific responses to similar levels of circulating T 3. Interestingly, NCoR recruitment to LXR is also impaired in this model, leading to activation of LXRtarget genes, further demonstrating that NCoR recruitment regulates multiple nuclear receptor signaling pathways.gene expression ͉ thyroid hormone receptor

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Determination of Nuclear Receptor Corepressor Interactions with the Thyroid Hormone Receptor

Cited by 73 publications

References 37 publications

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

The nuclear corepressor, NCoR, regulates thyroid hormone action in vivo

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