Dominant Negative and DNA-Binding Properties of Mutant Thyroid Hormone Receptors That Are Defective in Homodimerization But Not Heterodimerization

Thyroid ◽  
1995 ◽  
Vol 5 (5) ◽  
pp. 343-353 ◽  
Author(s):  
KOICHI KITAJIMA ◽  
TAKASHI NAGAYA ◽  
J. LARRY JAMESON
Keyword(s):  
Thyroid Hormone ◽  
Dna Binding ◽  
Hormone Receptors ◽  
Dominant Negative ◽  
Thyroid Hormone Receptors ◽  
Binding Properties ◽  
Dna Binding Properties

scholarly journals Thyroid hormone alters the DNA binding properties of chicken thyroid hormone receptors α and β

1992 ◽  
Vol 20 (18) ◽  
pp. 4803-4810 ◽  
Author(s):  
Monika L. Andersson ◽  
Kristina Nordström ◽  
Stephen Demczuk ◽  
Matthias Harbers ◽  
Björn Vennström
Keyword(s):  
Thyroid Hormone ◽  
Dna Binding ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptors ◽  
Binding Properties ◽  
Dna Binding Properties

scholarly journals Differential Recruitment of Nuclear Coregulators Directs the Isoform-Dependent Action of Mutant Thyroid Hormone Receptors

2011 ◽  
Vol 25 (6) ◽  
pp. 908-921 ◽  
Author(s):  
Laura Fozzatti ◽  
Changxue Lu ◽  
Dong-Wook Kim ◽  
Sheue-yann Cheng
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Biological Activities ◽  
Liver Lipid ◽  
Dominant Negative ◽  
Mutant Mice ◽  
Regulatory Proteins ◽  
Thyroid Hormone Receptors ◽  
Dominant Negative Mutation

Abstract Studies using mice deficient in thyroid hormone receptors (TR) indicate that the two TR isoforms, TRα1 and TRβ1, in addition to mediating overlapping biological activities of the thyroid hormone, T3, also mediate distinct functions. Mice harboring an identical dominant negative mutation (denoted PV) at the C terminus of TRα1 (Thra1PV mice) or β1 (ThrbPV mice) also exhibit distinct phenotypes. These knockin mutant mice provide an opportunity to understand the molecular basis of isoform-dependent functions in vivo. Here we tested the hypothesis that the distinct functions of TR mutant isoforms are directed by a subset of nuclear regulatory proteins. Tandem-affinity chromatography of HeLa nuclear extracts showed that distinct 33 nuclear proteins including nuclear receptor corepressor (NCoR1) and six other proteins preferentially associated with TRα1PV or TRβ1PV, respectively. These results indicate that recruitment of nuclear regulatory proteins by TR mutants is subtype dependent. The involvement of NCoR1 in mediating the distinct liver phenotype of Thra1PV and ThrbPV mice was further explored. NCoR1 preferentially interacted with TRα1PV rather than with TRβ1PV. NCoR1 was recruited more avidly to the thyroid hormone response element-bound TRα1PV than to TRβ1PV in the promoter of the CCAAT/enhancer-binding protein α gene to repress its expression in the liver of Thra1PV mice, but not in ThrbPV mice. This preferential recruitment of NCoR1 by mutant isoforms could contribute, at least in part, to the distinct liver lipid phenotype of these mutant mice. The present study highlights a novel mechanism by which TR isoforms direct their selective functions via preferential recruitment of a subset of nuclear coregulatory proteins.

The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms

1993 ◽  
Vol 13 (10) ◽  
pp. 5970-5980
Author(s):  
H W Chen ◽  
M L Privalsky
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Nuclear Hormone Receptors ◽  
Dominant Negative Inhibitor ◽  
Dominant Negative Mutations ◽  
Microbial Systems ◽  
Dna Binding Properties ◽  
Activate Gene

Genetic lesions that function as dominant negative mutations in microbial systems have long been recognized. It is only relatively recently, however, that similar dominant negative mutations have been implicated as a basis for genetic and neoplastic disorders in vertebrates. We describe here a dissection of the actions of the erbA oncogene protein, an aberrant form of thyroid hormone receptor that acts as a dominant negative inhibitor of other nuclear hormone receptors. We demonstrate that the ErbA oncoprotein interferes with thyroid hormone and trans-retinoic acid receptors by competing for binding to the corresponding response elements. Heterodimerization of the ErbA oncoprotein with these receptors does not play an observable role in repression. In contrast, however, the ErbA oncoprotein does efficiently form a heterodimer with the retinoid X receptor (RXR) class of nuclear hormone receptors; complex formation enhances the DNA-binding properties of the ErbA protein but dramatically interferes with the ability of the RXR component to activate gene expression. Our results indicate that the erbA oncogene may play a previously unanticipated role in neoplasia by interfering with RXR function.

scholarly journals Interactions of Estrogen- and Thyroid Hormone Receptors on a Progesterone Receptor Estrogen Response Element (ERE) Sequence: a Comparison with the Vitellogenin A2 Consensus ERE

1997 ◽  
Vol 11 (11) ◽  
pp. 1581-1592 ◽  
Author(s):  
Roderick E. M. Scott ◽  
X. Sharon Wu-Peng ◽  
Paul M. Yen ◽  
William W. Chin ◽  
Donald W. Pfaff
Keyword(s):  
Thyroid Hormone ◽  
Dna Binding ◽  
Reproductive Behavior ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptors ◽  
Estrogen Response Element ◽  
Hormone Response ◽  
Response Element ◽  
Estrogen Response

Abstract The identification of hormone response elements in the promoter regions of hormonally regulated genes has revealed a striking similarity between the half-site of the estrogen-response element (ERE) and a consensus sequence constituting the thyroid hormone-response element. Because of the potential for thyroid hormone (T3) to affect estrogen (E)- and progesterone-dependent female reproductive behavior via EREs, we have begun to investigate the activity of an ERE identified in the progesterone receptor (PR) proximal promoter and its interactions with the estrogen receptor (ER) and thyroid hormone receptors (TR). In addition, we have compared ER and TR interactions on the PR ERE construct with that of the vitellogenin A2 (vit A2) consensus ERE. Electrophoretic mobility shift assays demonstrated that TR binds to the PR ERE as well as to the consensus ERE sequence in vitro. Further, these two EREs were differentially regulated by T3 in the presence of TR. T3 in the presence of TRα increased transcription from a PR ERE construct ∼5-fold and had no inhibitory effect on E induction. Similarly, T3 also activated a β-galactosidase reporter construct containing PR promoter sequences spanning −1400 to +700. In addition, the TR isoforms β1 and β2 also stimulated transcription from the PR ERE construct by 5- to 6-fold. A TRα mutant lacking the ability to bind AGGTCA sequences in vitro failed to activate transcription from the PR ERE construct, demonstrating dependence on DNA binding. In contrast to its actions on the PR ERE construct, TRα did not activate transcription from the vit A2 consensus ERE but rather attenuated E-mediated transcriptional activation. Attenuation from the vit A2 consensus ERE is not necessarily dependent on DNA binding as the TRα DNA binding mutant was still able to inhibit E-dependent transactivation. In contrast to TRα, the isoforms TRβ1 and TRβ2 failed to inhibit E-induced activation from the vit A2 consensus ERE. These results demonstrate that the PR ERE construct differs from the vit A2 consensus ERE in its ability to respond to TRs and that divergent pathways exist for activation and inhibition by TR. Since ERs, PRs, and TRs are all present in hypothalamic neurons, these findings may be significant for endocrine integration, which is important for reproductive behavior.

scholarly journals Thyroid Hormone Receptors Control Developmental Maturation of the Middle Ear and the Size of the Ossicular Bones

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1548-1560 ◽  
Author(s):  
Emily A. Cordas ◽  
Lily Ng ◽  
Arturo Hernandez ◽  
Masahiro Kaneshige ◽  
Sheue-Yann Cheng ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Inner Ear ◽  
Middle Ear ◽  
Hormone Receptors ◽  
Dominant Negative ◽  
Thyroid Hormone Receptors ◽  
Auditory Thresholds ◽  
Auditory Development ◽  
Genes Encoding

Thyroid hormone is critical for auditory development and has well-known actions in the inner ear. However, less is known of thyroid hormone functions in the middle ear, which contains the ossicles (malleus, incus, stapes) that relay mechanical sound vibrations from the outer ear to the inner ear. During the later stages of middle ear development, prior to the onset of hearing, middle ear cavitation occurs, involving clearance of mesenchyme from the middle ear cavity while the immature cartilaginous ossicles attain appropriate size and ossify. Using in situ hybridization, we detected expression of Thra and Thrb genes encoding thyroid hormone receptors α1 and β (TRα1 and TRβ, respectively) in the immature ossicles, surrounding mesenchyme and tympanic membrane in the mouse. Thra+/PV mice that express a dominant-negative TRα1 protein exhibited deafness with elevated auditory thresholds and a range of middle ear abnormalities including chronic persistence of mesenchyme in the middle ear into adulthood, markedly enlarged ossicles, and delayed ossification of the ossicles. Congenitally hypothyroid Tshr−/− mice and TR-deficient Thra1−/−;Thrb−/− mice displayed similar abnormalities. These findings demonstrate that middle ear maturation is TR dependent and suggest that the middle ear is a sensitive target for thyroid hormone in development.

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.

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