Differential capacity of wild type promoter elements for binding and trans-activation by retinoic acid and thyroid hormone receptors.

Human thyroid hormone receptor (TR) is encoded by two distinct genes, TR alpha and TR beta. TR heterodimerizes with retinoid X receptor (RXR) and binds efficiently to the thyroid hormone (T(3)) response element (TRE) of target genes. In the absence of T(3), unliganded TR suppresses the basal promoter activity of positively regulated genes (silencing). Silencing mediator for retinoid and thyroid hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR) interact with unliganded TR and function as corepressor proteins. Previously, we found beta F451X with carboxyl (C)-terminal 11-amino acid deletion had stronger silencing potency than wild-type TR beta 1 and beta E449X with C-terminal 13-amino acid deletion on a subset of TREs. In the present study, to assess the isoform-specific effects of the C-terminal truncations on TR silencing, we constructed two mutant TR alpha 1s (alpha F397X and alpha E395X) with the same respective C-terminal truncations as beta F451X and beta E449X and analysed their silencing activities. Unlike beta F451X and beta E449X, alpha F397X and alpha E395X showed similarly stronger silencing potency than wild-type TR alpha 1. We further studied the abilities of wild-type and the mutant TR beta 1s and alpha 1s on RXR and co-repressor binding by a two-hybrid interference assay. beta F451X had significantly stronger abilities to bind to RXR and SMRT than did wild-type TR beta 1 and beta E449X. In contrast, wild-type TR alpha 1, alpha F397X and alpha E395X showed similar abilities to bind to RXR and SMRT. beta E449X and alpha E395X, which have identical C-terminal truncation, showed less ability to bind to N-CoR than did wild-type TR beta 1 and beta F451X and wild-type TR alpha 1 and alpha F397X respectively. These results indicate that an identical C-terminal truncation gives rise to different effects on TR beta 1 and alpha1 with respect to silencing potency, RXR binding and SMRT binding. The difference in the silencing potency among wild-type TR beta 1, beta F451X and beta E449X correlated well with the difference in the ability to bind co-repressor SMRT.

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Post-transcriptional induction of β1-adrenergic receptor by retinoic acid, but not triiodothyronine, in C6 glioma cells expressing thyroid hormone receptors

Acta Endocrinologica ◽

10.1530/eje.0.1350709 ◽

1996 ◽

Vol 135 (6) ◽

pp. 709-715 ◽

Cited By ~ 4

Author(s):

Mònica López-Barahona ◽

Teresa Iglesias ◽

Irene García-Higuera ◽

Federico Mayor ◽

Angel Zaballos ◽

...

Keyword(s):

Retinoic Acid ◽

Thyroid Hormone ◽

Adrenergic Receptor ◽

Hormone Receptors ◽

Glioma Cells ◽

C6 Glioma ◽

High Expression ◽

Thyroid Hormone Receptors ◽

C6 Glioma Cells ◽

C6 Cells

López-Barahona M, Iglesias T, García-Higuera I, Mayor Jr F, Zaballos A, Bernal J, Muñoz A. Posttranscriptional induction of β1 -adrenergic receptor by retinoic acid, but not triiodothyronine, in C6 glioma cells expressing thyroid hormone receptors. Eur J Endocrinol 1996:135:709–15. ISSN 0804–4643 Thyroid hormone (triiodothyronine; T3) has been shown to control the expression of β1 -adrenergic receptors (β1-AR) in cardiac myocytes, but not in C6 glioma cells. This cell specificity has been attributed to low expression of T3 receptors and high expression of the c-erbAα2 splice variant that interferes with the action of T3. To check this hypothesis we have expressed the c-erbA/thyroid hormone receptor (TR) α1 gene in C6 glioma cells and investigated their response to thyroid hormone. Cells expressing TRα1, but not wild-type cells, were responsive to T3 as shown by increased expression of mitochrondrial hydroxymethylglutaryl CoA synthase after T3 exposure. However, T3 had no effect on β1-AR gene expression in either set of cells. The β1-AR mRNA concentrations were, however, altered by retinoic acid (RA) treatment. Retinoic acid caused a rapid up-regulation of β1-AR mRNA levels that was blocked by cycloheximide. Retinoic acid did not increase the β1-AR gene transcription rate in run-on experiments. These results indicate an indirect post-transcriptional effect of RA. Control of β1-AR expression in C6 cells is also exerted at the translational level, because there was no correlation between mRNA and protein induction, as determined by radioligand binding studies. We conclude that lack of responsiveness of the β1-AR gene in C6 cells to T3 is not due to high expression of c-erbAα2 but to undefined cell-specific factors. Alberto Muñoz, Instituto Investigaciones Biomedicas, Arturo Duperier 4, 28029 Madrid, Spain

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The Book of Opposites: The Role of the Nuclear Receptor Co-regulators in the Suppression of Epidermal Genes by Retinoic Acid and Thyroid Hormone Receptors

Journal of Investigative Dermatology ◽

10.1111/j.0022-202x.2005.23691.x ◽

2005 ◽

Vol 124 (5) ◽

pp. 1034-1043 ◽

Cited By ~ 21

Author(s):

Sang H. Jho ◽

Constantinos Vouthounis ◽

Brian Lee ◽

Olivera Stojadinovic ◽

Mark J. Im ◽

...

Keyword(s):

Retinoic Acid ◽

Thyroid Hormone ◽

Nuclear Receptor ◽

Hormone Receptors ◽

Thyroid Hormone Receptors

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Heterodimeric interaction of the retinoic acid and thyroid hormone receptors in transcriptional regulation on the gamma F-crystallin everted retinoic acid response element.

Molecular Endocrinology ◽

10.1210/mend.8.11.7877618 ◽

1994 ◽

Vol 8 (11) ◽

pp. 1494-1506

Author(s):

M Tini ◽

L C Tsui ◽

V Giguère

Keyword(s):

Transcriptional Regulation ◽

Retinoic Acid ◽

Thyroid Hormone ◽

Hormone Receptors ◽

Thyroid Hormone Receptors ◽

Response Element ◽

Retinoic Acid Response Element

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Thyroid function and effect of aging in combined hetero/homozygous mice deficient in thyroid hormone receptors alpha and beta genes

Journal of Endocrinology ◽

10.1677/joe.0.1720177 ◽

2002 ◽

Vol 172 (1) ◽

pp. 177-185 ◽

Cited By ~ 21

Author(s):

RE Weiss ◽

O Chassande ◽

EK Koo ◽

PE Macchia ◽

K Cua ◽

...

Keyword(s):

Thyroid Hormone ◽

Thyroid Function ◽

Hormone Receptors ◽

Thyroid Hormone Receptors ◽

Thyroid Function Tests ◽

Wild Type ◽

Heterozygous Mouse ◽

Tsh Secretion ◽

Homozygous Deletions ◽

Serum Tsh

The maintenance of thyroid hormone (TH) homeostasis is dependent on the synthesis and secretion of TH regulated by TSH. This is achieved, in turn, by the negative feedback of TH on TSH secretion and synthesis, which requires the interaction with TH receptors (TRs). Derived by alternative splicing of two gene transcription products, three TRs (TRbeta1, TRbeta2 and TRalpha1) interact with TH while another, TRalpha2, binds to DNA but not to TH. In this study we compare the results of thyroid function tests in mice with deletions of the TRalpha and TRbeta genes alone and present novel data on mice that are double homozygous and combined heterozygous. Homozygous deletions of both the TRalpha and TRbeta in the same mouse (TRalphao/o; TRbeta-/-) resulted in serum TSH values only slightly lower than those in athyreotic, Pax8 knockout mice. Whereas the absence of TRalpha alone does not cause resistance to TH, the absence of TRbeta in the presence of TRalpha results in a 205, 169, 544% increase in serum thyroxine (T(4)), triiodothyronine (T(3)) and TSH concentrations respectively. However, in the absence of TRbeta, loss of one TRalpha allele can worsen the resistance to TH with a 243 and 307% increase in T(4) and T(3) respectively. Similarly, while the heterozygous mouse with a single TRbeta allele shows no alteration in thyroid function, the concomitant deletion of TRalpha brings about mild but significant resistance to TH. Furthermore, the severity of the resistance to TH was noted to decrease with age in parallel with the decrease in serum free T(4) values also seen in wild-type mice. These results demonstrate that (1) unliganded TRalpha or TRbeta are not absolutely necessary for the upregulation of TSH; (2) TRbeta but not TRalpha is sufficient for TH-mediated downregulation of TSH; and (3) TRalpha may partially substitute for TRbeta in mediating a partial TH-dependent TSH suppression.

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