Retinoic acid decreases thyroid hormone receptor expression in pituitary GH1 cells (original) (raw)
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Life Sciences, 1993
Summarv In order to clarify the effect of retinoids on thyroid cell growth and function, the presence of retinoic acid receptors (RARs) and the action of retinoic acid (RA) on DNA synthesis and on thyroid peroxidase (TPO) and thyroglobulin (TGB) mRNA expression were investigated in primary cultures of human thyroid follicular cells. A time and dose-dependent reduction in 3H-thymidine (3H-thy) incorporation was found in cells exposed for 48 h to all-trans-RA up to 1 ~tM. A cytotoxic effect was found only with the higher dose of 50 ~tM. The RA-induced decrease of 3H-thy incorporation was reflected by parallel change in DNA content of cell monolayers. The inhibitory effect of 1 I.tM RA on 3H-thy incorporation ranged from 28.5 + 4.6 % in normal cells to 42 +3.2 % in adenomatous cells. In addition, 1 ~tM RA significantly reduced basal and TSH-induced TPO mRNA levels in normal, goiu'ous and adenomatous ceils, but did not alter TGB mRNA levels. Furthermore, in these cells the study of RARct and B mRNA showed the presence of two major RARct mRNA transcripts of approximately 3.5 and 2.8 Kb in size, whereas RAR 13 mRNA was undetectable. Overall, our data indicate that RARct gene is expressed in human thyrocytes and that RA may be involved in the regulation of the human thyroid by reducing proliferation and function of follicular cells. The vitamin A derivative retinoic acid (RA) may play a fundamental role in regulating the growth and differentiation of a vmiety of cells (1). The cellular responses to RA are mediated by the binding to nuclear receptor proteins that are members of the steroid/thyroid hormone receptor superfamily of transcriptional regulators (2). Retinoids have been shown to affect thyroid function "in vivo". Vitamin A deficiency in rats has been found to be associated with an increase in serum concentrations of thyroid hormones (3). On the other hand, massive doses of vitamin A seem to inhibit thyroid function in man (4). In order to verify the possible role of RA in the regulation of growth and differentiation of the human thyroid we examined in primary cultures of human follicular cells the effect of RA on 3H
Retinoic acid effects on thyroid function of female rats
Life Sciences, 2009
Aims: Retinoic acid is widely used in dermatological treatment and thyroid cancer management; however its possible side-effects on normal thyroid function remains unknown. We aimed to determine the effects of retinoic acid on thyroid function of adult female rats. Main methods: Female Wistar rats were treated with all-trans-retinoic acid and 13-cis retinoic acid for 14 and 28 days. Then, rats were killed and thyroid function was evaluated. Key findings: Serum T4 and thyrotropin levels remained unchanged, while serum T3 increased in animals treated with all-trans-retinoic acid for 14 days. No changes were observed in hepatic or renal type 1 iodothyronine deiodinase (D1) activities, while thyroid D1 was higher in animals treated for 14 days with alltrans-retinoic acid, which could be related to the increased serum T3 levels. 13-cis retinoic acid increased thyroid iodide uptake after 28 days. These results show effects of retinoic acid treatment on these thyroid proteins: sodium/iodide symporter and deiodinase. Significance: Retinoic acid is able to interfere with normal thyroid function, increasing thyroid type 1 deiodinase activity, serum T3 levels and sodium/iodide symporter function. However, the effects are timeand retinoic acid isomer-dependent. Since serum thyrotropin levels did not change in any group, the effects observed are probably mediated by a direct retinoic acid effect on the normal thyroid.
Regulation of thyroid hormone receptor β-2 mRNA levels by retinoic acid
Molecular and Cellular Endocrinology, 1993
The thyroid hormone receptor, TR p-2, whose expression is limited to the pituitary and parts of the central nervous system, is strongly negatively regulated at the pre-translational level by thyroid hormone (T3). We have investigated whether retinoic acid (RA), whose receptors (RARs) share a high degree of homology with the thyroid hormone receptors (TRs), can regulate this gene in a manner simiIar to T3, as has been shown for the growth hormone (GH) gene. GH3 cells were incubated with 10 nM T3,l FM RA or both for 48 h and then TR p-2 mRNA levels determined by RNA blot hybridization analysis. We observed a 73% decrease in TR p-2 mRNA levels after incubation with T3 and a twofold increase in TR p-2 mRNA levels after incubation with RA alone. In the presence of RA, the T3 effect on TR p-2 mRNA levels was blunted with mRNA levels decreasing by only 20%. We investigated the mechanism by which retinoic acid increases and opposes the effects of T3 on levels of TR p-2 mRNA. In transient transfection experiments using a reporter plasmid containing the TR p-2 promoter and in nuclear run on assays, we found no effect of RA on TR p-2 gene transcription. We then investigated whether the effects of RA were mediated at the post-transcriptional level. Determination of the apparent half-life of TR p-2 mRNA using the transcriptional inhibitor, a~tinomycin D, showed that RA had no effect on TR p-2 mRNA stability. Therefore, we conclude that RA regulates another post-transcriptional event, either processing or transport of the TR p-2 mRNA.
Retinol oxidation to retinoic acid in human thyroid glandular cells
Journal of Enzyme Inhibition and Medicinal Chemistry, 2014
Retinoic acid is regarded as the retinol metabolite that controls proliferation and differentiation of epithelial cells. In the present study, we investigated the potential role of xanthine dehydrogenase (XDH) in retinoic acid biosynthesis in human thyroid glandular cells (HTGC). In particular, we observed that cellular retinoids binding proteins (CRBPs) are also implicated in the biosynthetic pathway leading to retinoic acid formation in primary cultures of HTGC, as we have already reported for human mammary epithelial cells (HMEC). After partial protein purification, the enzyme responsible for retinoic acid biosynthesis was identified and quantified as XDH by immunoassay, by its ability to oxidize xanthine to uric acid and its sensitivity to the inhibitory effect of oxypurinol. The evidence of XDH-driven formation of retinoic acid in HTGC cultures further corroborates the potential role of XDH in retinoic acid biosynthesis in the epithelia.
British Journal of Nutrition, 2003
Recent studies have revealed that retinoids play an important role in the adult central nervous system and cognitive functions. Previous investigations in mice have shown that vitamin A deficiency (VAD) generates a hypo-expression of retinoic acid (RA, the active metabolite of vitamin A) receptors and of neurogranin (RC3, a neuronal protein involved in synaptic plasticity) and a concomitant selective behavioural impairment. Knowing that RC3 is both a triiodothyronine (T 3 ) and a RA target gene, and in consideration of the relationships between the signalling pathways of retinoids and thyroid hormones, the involvement of T 3 on RA signalling functionality in VAD was investigated. Thus, the effects of vitamin A depletion and subsequent administration with RA and/or T 3 on the expression of RA nuclear receptors (RAR, RXR), T 3 nuclear receptor (TR) and on RC3 in the brain were examined. Rats fed a vitamin A-deficient diet for 10 weeks exhibited a decreased expression of RAR, RXR and TR mRNA and of RC3 mRNA and proteins. RA administration to these vitamin A-deficient rats reversed only the RA hypo-signalling in the brain. Interestingly, T 3 is able to restore its own brain signalling simultaneously with that of vitamin A and the hypo-expression of RC3. These results obtained in vivo revealed that one of the consequences of VAD is a dysfunction in the thyroid signalling pathway in the brain. This seems of crucial importance since the down regulation of RC3 observed in the depleted rats was corrected only by T 3 .
Retinol has specific effects on binding of thyrotrophin to cultured porcine thyrocytes
Journal of Endocrinology, 2004
Retinoids are potential candidates for the treatment of thyroid cancer. However, one of the disadvantages of these substances is their dedifferentiating effect on normal non-transformed thyrocytes. To identify conditions under which no dedifferentiating effect of retinol on normal thyrocytes can be observed, we determined iodide uptake, protein iodination, expression of sodium-iodide symporter (NIS) mRNA and protein, and the binding of iodine-125labelled bTSH in cultured porcine thyrocytes. Combination of TSH and c6·5 µM retinol increased iodide uptake and protein iodination compared with TSH alone over the entire incubation time, whereas TSH plus d13 µM retinol increased the uptake of iodine-125 only during the first 12 h but decreased it after 30 h and longer. After d30 h incubation times with d13 µM retinol, the fraction of apoptotic cells was enhanced and proliferation decreased. The incubation with retinol enhanced the binding of [ 125 I]bTSH to thyrocytes, but did not influence expression of the NIS. With low retinol concentrations, the effect on the binding of TSH apparently predominated and retinol increased thyroid function; with higher concentrations the pro-apoptotic effect of retinol overlapped and a two-phased time course resulted. It can be concluded that low concentrations of retinol also exert differentiating effects in normal thyrocytes.
Journal of Molecular Endocrinology, 2005
In vivo assessment of the cellular impact of thyroid hormones on target tissues might be of help for physiological studies and to evaluate the consequences of various diseases of the thyroid gland in humans. Given the tenuous relationship between retinoid and tri-iodothyronine (T 3 ) status and that retinoids have also intracellular roles, the aim of this study was to determine the effect of hypothyroidism on the expression of T 3 nuclear receptors (TR) and retinoic acid nuclear receptors (RAR, RXR) in human peripheral blood mononuclear cells (PBMC). Using real time RT-PCR, we quantified the relative amount of mRNA of the thyroid (TR and TR ) and retinoid (RAR , RAR , and RXR ) nuclear receptors in PBMC of euthyroid (n=22) compared with hypothyroid (n=22) subjects. Classical plasma parameters (free T 3 (FT 3 ), free thyroxine (T 4 ) (FT 4 ), thyroid-stimulating hormone (TSH), retinol (ROH), retinol-binding protein (RBP) and transthyretin (TTR)) were also measured. In hypothyroid subjects, the concentration of TSH was elevated, and dramatically low T 3 and T 4 concentrations were associated with a decrease in the expression of TR . Expression of RAR and RAR significantly decreased in hypothyroid versus control subjects, while an increased concentration of ROH was emphasised by hypothyroidism. These results first indicated that primary hypothyroidism induces hypoactivation of the retinoid nuclear pathway in PBMC, which was not predicted by the plasma ROH level. Further investigations will be necessary to evaluate these parameters in very small changes in thyroid hormone production such as mild (subclinical) hypothyroidism.