Positive and negative regulation of gene transcription by a retinoic acid-thyroid hormone receptor heterodimer

Cell ◽  
1989 ◽  
Vol 59 (4) ◽  
pp. 697-708 ◽  
Author(s):  
Christopher K. Glass ◽  
Steven M. Lipkin ◽  
Orly V. Devary ◽  
Michael G. Rosenfeld
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Gene Transcription ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Negative Regulation

scholarly journals The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription

2008 ◽  
Vol 41 (1) ◽  
pp. 25-34 ◽  
Author(s):  
Anne Wulf ◽  
Marianne G Wetzel ◽  
Maxim Kebenko ◽  
Meike Kröger ◽  
Angelika Harneit ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Dna Binding ◽  
Gene Transcription ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Point Mutations ◽  
Chimeric Protein ◽  
Functional Consequences ◽  
Glycerol 3 Phosphate Dehydrogenase

Thyroid hormone 3,3′,5-tri-iodothyronine (T3) regulates gene expression in a positive and negative manner. Here, we analyzed the regulation of a positively (mitochondrial glycerol-3-phosphate dehydrogenase) and negatively T3-regulated target gene (TSHα). Thyroid hormone receptor (TR) activates mGPDH but not TSH promoter fragments in a mammalian one-hybrid assay. Furthermore, we investigated functional consequences of targeting TR to DNA independent of its own DNA-binding domain (DBD). Using a chimeric fusion protein of the DBD of yeast transcription factor Gal4 with TR, we demonstrated a positive regulation of gene transcription in response to T3. T3-mediated activation of this chimeric protein is further increased after an introduction of point mutations within the DBD of TR. Moreover, we investigated the capacity of TR to negatively regulate gene transcription on a DNA-tethered cofactor platform. A direct binding of TR to DNA via its own DBD is dispensable in this assay. We investigated functional consequences of point mutations affecting different domains of TR. Our data indicate that the DBD of TR plays a key role in direct DNA binding on positively but not on negatively T3-regulated target genes. Nevertheless, the DBD is involved in mediating negative gene regulation independent of its capacity to bind DNA.

scholarly journals Thyroid-hormone-dependent negative regulation of thyrotropin beta gene by thyroid hormone receptors: study with a new experimental system using CV1 cells

2004 ◽  
Vol 378 (2) ◽  
pp. 549-557 ◽  
Author(s):  
Keiko NAKANO ◽  
Akio MATSUSHITA ◽  
Shigekazu SASAKI ◽  
Hiroko MISAWA ◽  
Kozo NISHIYAMA ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Experimental System ◽  
Thyroid Stimulating Hormone ◽  
Negative Regulation ◽  
Dominant Negative ◽  
Negative Effects ◽  
Receptor Isoforms

The molecular mechanism involved in the liganded thyroid hormone receptor suppression of the TSHβ (thyroid-stimulating hormone β, or thyrotropin β) gene transcription is undetermined. One of the main reasons is the limitation of useful cell lines for the experiments. We have developed an assay system using non-pituitary CV1 cells and studied the negative regulation of the TSHβ gene. In CV1 cells, the TSHβ–CAT (chloramphenicol acetyltransferase) reporter was stimulated by Pit1 and GATA2 and suppressed by T3 (3,3´,5-tri-iodothyronine)-bound thyroid hormone receptor. The suppression was dependent on the amounts of T3 and the receptor. Unliganded receptor did not stimulate TSHβ activity, suggesting that the receptor itself is not an activator. Analyses using various receptor mutants revealed that the intact DNA-binding domain is crucial to the TSHβ gene suppression. Co-activators and co-repressors are not necessarily essential, but are required for the full suppression of the TSHβ gene. Among the three receptor isoforms, β2 exhibited the strongest inhibition and its protein level was the most predominant in a thyrotroph cell line, TαT1, in Western blotting. The dominant-negative effects of various receptor mutants measured on the TSHβ–CAT reporter were not simple mirror images of those in the positive regulation under physiological T3 concentration.

scholarly journals Aberrant Expression of Thyroid Hormone Receptor β Isoform May Cause Inappropriate Secretion of TSH in a TSH-Secreting Pituitary Adenoma

2011 ◽  
Vol 96 (6) ◽  
pp. E948-E952 ◽  
Author(s):  
Tetsuya Tagami ◽  
Takeshi Usui ◽  
Akira Shimatsu ◽  
Mutsuo Beniko ◽  
Hiroyuki Yamamoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pituitary Adenoma ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Transient Gene Expression ◽  
Negative Regulation ◽  
Aberrant Expression ◽  
Inappropriate Secretion ◽  
Thyroid Hormone Receptor Β

Context: Patients with TSH-secreting pituitary adenomas (TSHoma) show inappropriate secretion of TSH; serum TSH levels are not suppressed despite high serum free thyroid hormone levels. The mechanism of a defect in negative regulation of TSH in a TSHoma is still unclear. Objective: Recently, we cloned a novel thyroid hormone receptor β isoform (TRβ4) from a human pituitary library. To elucidate the clinical significance of TRβ4, we investigated the expression of this isoform in TSHoma. Methods: RT-PCR was performed to detect TRβ isoforms such as TRβ1, TRβ2, and TRβ4 using RNA obtained from surgically resected TSHoma. The effects of TRβ4 on the TSH gene expression were examined in the transient gene expression experiments. Results: Quantitative analysis using a real-time PCR revealed that relative expression of TRβ4 to TRβ1+2 was higher in three TSHoma than in a prolactinoma or a nonfunctioning pituitary adenoma. TRβ4 construct did not mediate T3-dependent gene regulation but inhibited the negative regulation of TSHα mediated by TRβ1 or TRβ2. Conclusions: Aberrant expression of TRβ4 may partly contribute to the inappropriate secretion of TSH in a TSHoma.

scholarly journals Developmental Exposure to Bisphenol A Impairs the Uterine Response to Ovarian Steroids in the Adult

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5848-5860 ◽  
Author(s):  
Jorgelina Varayoud ◽  
Jorge G. Ramos ◽  
Verónica L. Bosquiazzo ◽  
Mónica Muñoz-de-Toro ◽  
Enrique H. Luque
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Bisphenol A ◽  
Hormone Receptor ◽  
Hox Genes ◽  
Thyroid Hormone Receptor ◽  
Developmental Trajectory ◽  
Ovariectomized Rats ◽  
Long Term Effects ◽  
Uterine Receptivity

Morphoregulator genes like members of the Hox gene family regulate uterine development and are associated with endocrine-related processes such as endometrial proliferation and differentiation in the adult uterus. Exposure to neonatal endocrine disruptors could affect signaling events governed by Hox genes, altering the developmental trajectory of the uterus with lasting consequences. We investigated whether neonatal exposure to bisphenol A (BPA) alters Hoxa10 and Hoxa11 mRNA uterine expression shortly after treatment as well as in the adult. Moreover, we studied whether xenoestrogen exposure may affect the adult uterine response to hormonal stimuli. Newborn females received vehicle, 0.05 mg/kg·d BPA, 20 mg/kg•d BPA, or diethylstilbestrol (0.2 μg/kg•d) on postnatal d 1, 3, 5, and 7). At postnatal d 8, real time RT-PCR assays showed a decrease in Hoxa10 and Hoxa11 expression in all xenoestrogen-treated groups. To evaluate the long-term effects, we used adult ovariectomized rats with hormonal replacement. The subepithelial stroma in BPA- and diethylstilbestrol-treated animals showed an impaired proliferative response to steroid treatment associated with a silencing of Hoxa10 but not associated with changes in the methylation pattern of the Hoxa10 promoter. BPA animals showed that the Hoxa10 reduction was accompanied by an increased stromal expression of the silencing mediator for retinoic acid and thyroid hormone receptor. The spatial coexpression of steroid receptors Hoxa10 and silencing mediator for retinoic acid and thyroid hormone receptor was established using immunofluorescence. Our data indicate that postnatal BPA exposure affects the steroid hormone-responsiveness of uterine stroma in adulthood. Whether this impaired hormonal response is associated with effects on uterine receptivity and decidualization is currently under investigation.

Sign in / Sign up

Export Citation Format

Share Document