scholarly journals Characterization of skeletal phenotypes of TRα1PV and TRβPV mutant mice: implications for tissue thyroid status and T3 target gene expression

2006 ◽  
Vol 4 (1) ◽  
pp. nrs.04011 ◽  
Author(s):  
Patrick J. O'Shea ◽  
J.H. Duncan Bassett ◽  
Sheue-yann Cheng ◽  
Graham R. Williams
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Target Gene ◽  
Thyroid Hormone Receptor ◽  
Bone Development ◽  
Negative Resistance ◽  
Dominant Negative ◽  
Thyroid Status ◽  
Target Gene Expression

Bone development is extremely sensitive to alterations in thyroid status. Recently, we analyzed the skeletal phenotypes of mice with the dominant negative resistance to thyroid hormone (RTH) mutation PV targeted to either the thyroid hormone receptor (TR) α1 or β gene. This perspective summarizes our findings to date and explores the wider implications for thyroid status and T3 target gene expression in individual tissues.

scholarly journals Cloning and Characterization of Two Novel Thyroid Hormone Receptor β Isoforms

2000 ◽  
Vol 20 (22) ◽  
pp. 8329-8342 ◽  
Author(s):  
Graham R. Williams
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Binding Activity ◽  
Dominant Negative ◽  
Thyroid Status ◽  
Alternative Mrna Splicing ◽  
Thyroid Hormone Receptor Β ◽  
Multiple Receptor ◽  
Functional Receptor

ABSTRACT Thyroid hormone (T3) activates nuclear receptor transcription factors, encoded by the TRα (NR1A1) and TRβ (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 T3 action. Thus, it is not known how diverse T3 actions are regulated in target tissues that express multiple receptor variants. I have identified two novel TRβ isoforms that are expressed widely and result from alternative mRNA splicing. TRβ3 is a 44.6-kDa protein that contains an unique 23-amino-acid N terminus and acts as a functional receptor. TRΔβ3 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 β3 and Δβ3 mRNAs vary between tissues and with changes in thyroid status, indicating that alternative splicing is tissue specific and T3 regulated. These data provide novel insights into the mechanisms of T3 action and define a new level of specificity that may regulate thyroid status in tissue.

scholarly journals Structure-guided approach to relieving transcriptional repression inResistance to Thyroid Hormone α

2021 ◽  
Author(s):  
Beatriz Romartinez-Alonso ◽  
Maura Agostini ◽  
Heulyn Jones ◽  
Jayde McLellan ◽  
Deepali Sood ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Transcriptional Repression ◽  
Target Gene ◽  
Thyroid Hormone Receptor ◽  
Activation Function ◽  
Zebrafish Model ◽  
Target Gene Expression ◽  
Corepressor Complex ◽  
Thyroid Hormone Receptor Α

Mutations in thyroid hormone receptor α (TRα), a ligand-inducible transcription factor, cause Resistance to Thyroid Hormone α (RTHα). This disorder is characterised by tissue-specific hormone refractoriness and hypothyroidism, due to inhibition of target gene expression by mutant TRα-corepressor complexes. Using biophysical approaches, we show that RTHα-associated TRα mutants devoid of ligand-dependent transcription activation function, unexpectedly retain the ability to bind thyroid hormone. Visualisation of ligand (T3) within the crystal structure of a prototypic TRα mutant, validates this notion. This finding prompted synthesis of different thyroid hormone analogues, identifying a lead compound (ES08) which dissociates corepressor from mutant human TRα more efficaciously than T3. ES08 rescues developmental anomalies in a zebrafish model of RTHα and induces target gene expression in TRα mutation-containing cells from an RTHα patient, more effectively than T3. Our observations provide proof-of-principle for developing synthetic ligands that can relieve transcriptional repression by the mutant TRα-corepressor complex, for treatment of RTHα.

Mutants of cubitus interruptus that are independent of PKA regulation are independent of hedgehog signaling

Development ◽  
1999 ◽  
Vol 126 (16) ◽  
pp. 3607-3616 ◽  
Author(s):  
Y. Chen ◽  
J.R. Cardinaux ◽  
R.H. Goodman ◽  
S.M. Smolik
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Ectopic Expression ◽  
Proteolytic Processing ◽  
Dominant Negative ◽  
Cubitus Interruptus ◽  
Target Gene Expression ◽  
Exogenous Expression

Hedgehog (HH) is an important morphogen involved in pattern formation during Drosophila embryogenesis and disc development. cubitus interruptus (ci) encodes a transcription factor responsible for transducing the hh signal in the nucleus and activating hh target gene expression. Previous studies have shown that CI exists in two forms: a 75 kDa proteolytic repressor form and a 155 kDa activator form. The ratio of these forms, which is regulated positively by hh signaling and negatively by PKA activity, determines the on/off status of hh target gene expression. In this paper, we demonstrate that the exogenous expression of CI that is mutant for four consensus PKA sites [CI(m1-4)], causes ectopic expression of wingless (wg) in vivo and a phenotype consistent with wg overexpression. Expression of CI(m1-4), but not CI(wt), can rescue the hh mutant phenotype and restore wg expression in hh mutant embryos. When PKA activity is suppressed by expressing a dominant negative PKA mutant, the exogenous expression of CI(wt) results in overexpression of wg and lethality in embryogenesis, defects that are similar to those caused by the exogenous expression of CI(m1-4). In addition, we demonstrate that, in cell culture, the mutation of any one of the three serine-containing PKA sites abolishes the proteolytic processing of CI. We also show that PKA directly phosphorylates the four consensus phosphorylation sites in vitro. Taken together, our results suggest that positive hh and negative PKA regulation of wg gene expression converge on the regulation of CI phosphorylation.

The dominant negative thyroid hormone receptor β-mutant Δ337T alters PPARα signaling in heart

2007 ◽  
Vol 292 (2) ◽  
pp. E453-E460 ◽  
Author(s):  
Norman E. Buroker ◽  
Martin E. Young ◽  
Caimiao Wei ◽  
Kyle Serikawa ◽  
Ming Ge ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Protein Content ◽  
Nuclear Receptors ◽  
Cross Talk ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Variable Cross ◽  
Multiple Genes

PPARα and TR independently regulate cardiac metabolism. Although ligands for both these receptors are currently under evaluation for treatment of congestive heart failure, their interactions or signaling cooperation have not been investigated in heart. We tested the hypothesis that cardiac TRs interact with PPARα regulation of target genes and used mice exhibiting a cardioselective Δ337T TRβ1 mutation (MUT) to reveal cross-talk between these nuclear receptors. This dominant negative transgene potently inhibits DNA binding for both wild-type (WT) TRα and TRβ. We used UCP3 and MTE-1 as principal reporters and analyzed gene expression from hearts of transgenic (MUT) and nontransgenic (WT) littermates 6 h after receiving either specific PPARα ligand (WY-14643) or vehicle. Interactions were determined through qRT-PCR analyses, and the extent of these interactions across multiple genes was determined using expression arrays. In the basal state, we detected no differences between groups for protein content for UCP3, PPARα, TRα2, RXRβ, or PGC-1α. However, protein content for TRα1 and the PPARα heterodimeric partner RXRα was diminished in MUT, whereas PPARβ increased. We demonstrated cross-talk between PPAR and TR for multiple genes, including the reporters UCP3 and MTE1. WY-14643 induced a twofold increase in UCP3 gene expression that was totally abrogated in MUT. We demonstrated variable cross-talk patterns, indicating that multiple mechanisms operate according to individual target genes. The non-ligand-binding TRβ1 mutation alters expression for multiple nuclear receptors, providing a novel mechanism for interaction that has not been previously demonstrated. These results indicate that therapeutic response to PPARα ligands may be determined by thyroid hormone state and TR function.

scholarly journals Hematopoiesis in aged female mice devoid of thyroid hormone receptors

2020 ◽  
Vol 244 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Ángela Sánchez ◽  
Constanza Contreras-Jurado ◽  
Diego Rodríguez ◽  
Javier Regadera ◽  
Susana Alemany ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
B Cell ◽  
Knockout Mice ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Thyroid Hormone Receptors ◽  
Female Mice

Hypothyroidism is often associated with anemia and immunological disorders. Similar defects are found in patients and in mice with a mutated dominant-negative thyroid hormone receptor α (TRα) and in knockout mice devoid of this receptor, suggesting that this isoform is responsible for the effects of the thyroid hormones in hematopoiesis. However, the hematological phenotype of mice lacking also TRβ has not yet been examined. We show here that TRα1/TRβ-knockout female mice, lacking all known thyroid hormone receptors with capacity to bind thyroid hormones, do not have overt anemia and in contrast with hypothyroid mice do not present reduced Gata1 or Hif1 gene expression. Similar to that found in hypothyroidism or TRα deficiency during the juvenile period, the B-cell population is reduced in the spleen and bone marrow of ageing TRα1/TRβ-knockout mice, suggesting that TRβ does not play a major role in B-cell development. However, splenic hypotrophy is more marked in hypothyroid mice than in TRα1/TRβ-knockout mice and the splenic population of T-lymphocytes is not significantly impaired in these mice in contrast with the reduction found in hypothyroidism. Our results show that the overall hematopoietic phenotype of the TRα1/TRβ-knockout mice is milder than that found in the absence of hormone. Although other mechanism/s cannot be ruled out, our results suggest that the unoccupied TRs could have a negative effect on hematopoiesis, likely secondary to repression of hematopoietic gene expression.

scholarly journals Thyroid hormone status interferes with estrogen target gene expression in breast cancer samples of menopausal women

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Sandro José Conde ◽  
Renata de Azevedo M. Luvizotto ◽  
Maria Teresa Síbio ◽  
Célia Regina Nogueira
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Thyroid Hormone ◽  
Target Gene ◽  
Target Gene Expression ◽  
Menopausal Women ◽  
Hormone Status

The corepressor Alien as a novel tumor suppressor?

2011 ◽  
Vol 5 (1) ◽  
Author(s):  
Aria Baniahmad
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Gene Silencing ◽  
Hormone Receptor ◽  
Cell Cycle Progression ◽  
Target Gene ◽  
Thyroid Hormone Receptor ◽  
Cycle Progression ◽  
Target Gene Expression ◽  
Proteomic Approach

AbstractAlien has been characterized as a corepressor for nuclear hormone receptors that harbor a silencing domain such as the thyroid hormone receptor (TR), the vitamin D3 receptor (VDR) and DAX-1. In addition, the androgen receptor (AR), a steroid hormone receptor, interacts with Alien. Alien enhances gene silencing mediated by TR, VDR and DAX-1, whereas Alien inhibits AR-mediated transactivation. The inhibition of AR by Alien seems to be restricted to cases where AR is bound to AR antagonists. In line with this, Alien inhibits AR target gene expression and human prostate cancer cell proliferation in an antagonist-specific manner indicating that Alien has an inhibitory role for cell cycle progression. Alien mediates gene silencing by recruitment of histone deacetylase activity and interestingly through nucleo-some assembly activity. Hereby, Alien enhances nucleosome positioning mediated by nucleosome assembly protein 1, which suggests a novel molecular mechanism of corepressor function. Using a proteomic approach to identify Alien interacting partners, we detected the cell cycle factor E2F1 to bind to Alien in vivo. The E2F1-mediated transactivation and E2F target gene expression is inhibited by Alien, and in line with this Alien is observed to repress cell cycle progression.

Dimerization: a versatile switch for oncogenesis

Blood ◽  
2004 ◽  
Vol 104 (4) ◽  
pp. 919-922 ◽  
Author(s):  
Chi Wai So ◽  
Michael L. Cleary
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Chromosomal Rearrangements ◽  
Dominant Negative ◽  
Negative Effects ◽  
Acute Leukemias ◽  
Target Gene Expression ◽  
Transcriptional Cofactors ◽  
Basal Transcriptional Machinery ◽  
Self Association

AbstractForced dimerization or oligomerization has emerged as a powerful mechanism for unleashing the oncogenic properties of chimeric transcription factors in acute leukemias. Fusion of transcriptional regulators with a variety of heterologous partner proteins as a consequence of chromosomal rearrangements induces inappropriate self-association, leading to aberrant transcriptional properties and leukemogenesis. Forced dimerization/oligomerization may alter the association of a DNA-binding protein for its transcriptional cofactors, or the dimerization motifs themselves may constitutively recruit transcriptional effector molecules. Oligomerized chimeras may also sequester essential partners or cofactors to exert dominant-negative effects on target gene expression. A key mechanistic feature, and one with major clinical implications, is the nature of the transcriptional cofactors that are recruited by the dimerized oncoprotein. Chimeric RARα and acute myeloid leukemia 1 (AML1) proteins induce constitutive repression after the recruitment of corepressors, whereas inappropriate maintenance of target gene expression by mixed-lineage leukemia (MLL) chimeras may result from the recruitment of coactivators or the basal transcriptional machinery. Molecular therapies directed at enzymatic activities of the aberrantly recruited cofactors, or antagonism of dimerization itself, represent promising avenues of current and future investigation.

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