Thyroid Hormone Receptor Family Research Articles

Endothelial and Vascular Muscle PPARγ in Arterial Pressure Regulation

Peroxisome proliferator-activated receptor gamma (PPARγ, NR1C3) is a ligand-activated transcription factor belonging to the retinoic acid receptor and thyroid hormone receptor family of nuclear receptors. Classically, these transcription factors regulate expression of target genes by binding to PPAR response elements (PPRE) in the 5′ flanking region of target genes as a heterodimer with retinoid X receptors (RXR). PPARγ first gained prominence when it was discovered that it was expressed specifically in adipocytes and its expression induced their differentiation.1 It has now become clear that although expression of PPARγ may be the highest in adipose tissue, it is expressed in many, if not all, cell types and tissues. Among the many roles ascribed to PPARγ are adipogenesis, insulin action, glucose homeostasis, and lipid metabolism. Other tissue-specific functions for PPARγ in liver, muscle, heart, macrophages, bone, and, more recently, the vasculature have been proposed, ascribed mainly from the analysis of cultured cells and a large and rapidly expanding set of tissue-specific PPARγ knockouts. The standing of PPARγ as a clinically important molecule emerged when it was discovered that PPARγ is the molecular target of the thiazolidinediones (TZD) class of antidiabetic agents.2 Although of understandable interest to diabetes researchers and clinicians, interest among “hypertensionists” increased when it became clear that TZD, in addition to improving glycemic control, tended to lower blood pressure. Many of these studies involved high-risk patients with diabetes or metabolic syndrome and an average decrease of ≈5 mmHg systolic blood pressure and 3 mmHg (diastolic blood pressure [DBP]) was typically reported. According to guidelines from the American Heart Association, 65 million Americans have hypertension and millions of others have prehypertension. Therefore, an analysis of any drug effective at lowering arterial pressure or physiological pathway targeted by that drug involved in regulating arterial pressure deserves serious attention. In this …

Environment and endocrinology: The case of thyroidology

Evidence is accumulating for interference of selected endocrine disrupting chemicals (EDC) with the thyroid axis. EDC disturb thyroid hormone (TH) homeostasis leading to developmental defects, hypothyroidism and altered thyroid growth patterns. A rising incidence of papillary thyroid carcinoma (PTC) in several Western countries cannot be definitely accounted for by improved diagnosis or management of thyroid cancer or improved iodine supply. In recent studies, we and others detected, within the thyroid hormone axis, multiple molecular targets of disruption by EDC, which are used in cosmetics, as pesticides or plasticizers or consumed as plant-derived compounds with the diet or with nutritional supplements. Several of these agents exert adverse effects on thyroid growth and function in animal or in vitro cellular models. Major targets are the sodium iodide symporter (NIS), the hemoprotein thyroperoxidase (TPO), the T4 distributor protein transthyretin (TTR), the deiodinases, TH conjugating enzymes and the TR thyroid hormone receptor family. Still prevailing iodine deficiency in many parts of the world predisposes the thyroid gland to adverse effects of endocrine disrupters especially under phases of vulnerability during development and under adaptive challenges during diseases.

Dopamine and serotonin interactions in the modulation of the expression of the immediate-early transcription factor, nerve growth factor-inducible B, in the striatum

Nerve growth factor-inducible B is a closely related member of the steroid–thyroid hormone receptor family of ligand-activated transcription factor. Recent evidence suggests a close relationship between nerve growth factor-inducible B and the dopamine system. Basal expression of messenger RNA for nerve growth factor-inducible B is relatively high in the striatum. The aims of the present study were: (i) to study the basal distribution and the modulation of striatal nerve growth factor-inducible B messenger RNA expression by dopamine and serotonin agonists, and (ii) to investigate the effects of combined administration of dopamine (D) and serotonin (5-HT) agonists. First, we investigated the effects of SKF38393 (D 1), quinpirole (D 2), 8-hydroxy-2-(di- n-propylaminotetralin) (5-HT 1A) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (5-HT 2A/2C) administered alone on striatal nerve growth factor-inducible B messenger RNA expression. In a second series of experiments, the effects of a combined administration of dopamine D 1 and serotonin 5-HT 1A or 5-HT 2A/2C agonists were studied. The goal of the last series of experiments was to determine the effects of a combined administration of the dopamine D 2 agonist and either serotonin 5-HT 1A or 5-HT 2A/2C agonists. Our results show that: (i) striatal nerve growth factor-inducible B messenger RNA expression exhibited a lateral–medial gradient in drug-naive rats, (ii) quinpirole and 8-hydroxy-2-(di- n-propylaminotetralin) administered alone induced a significant decrease in striatal nerve growth factor-inducible B messenger RNA expression while 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane significantly increased it, (iii) complex interactions were found when dopamine D 1 and serotonin 5-HT 1A or 5-HT 2A/2C agonists were administered in combination, and (iv) combined administration of quinpirole and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane resulted in a significant decrease in nerve growth factor-inducible B expression. Taken together, these results demonstrate that striatal nerve growth factor-inducible B messenger RNA expression can be modulated by both dopamine and serotonin agonists. They also point out the existence of complex interactions between dopamine and serotonin in regard to striatal expression of the immediate-early transcription factor nerve growth factor-inducible B.

Nurr1 mRNA expression in neonatal and adult rat brain following kainic acid-induced seizure activity

Nurr1 is an immediate early gene encoding a member of the steroid–thyroid hormone receptor family. In PC12 cells, Nurr1 is readily induced by membrane depolarization, but not by growth factors. Nurr1 is predominantly expressed in the brain, and is essential to the differentiation of midbrain dopaminergic neurons. However, Nurr1 is also expressed in brain regions unrelated to dopaminergic neurons, e.g., hippocampus and cerebral cortex, and its immediate induction following seizure activity suggests a potential involvement of this transcription factor in modulating gene expression in the nervous system. To investigate the response of Nurr1 to neuronal activation, we analyzed Nurr1 mRNA expression in neonatal and adult rat brain following kainic acid (KA)-induced seizure. In P7 animals, systemic injection of KA increased Nurr1 mRNA levels in a few hilar cells of the dentate gyrus and some pyramidal cells of the CA3 region of the hippocampus. In older animals, Nurr1 induction progressively expanded to all hippocampal regions (P14, P21) and eventually to cortical regions (adult). The increase was rapid and transient in the dentate gyrus, a structure resistant to the neurotoxic effect of KA, and was more prolonged in other regions more susceptible to KA toxicity. Induction of Nurr1 at early postnatal stages and rapid increase in the dentate gyrus following KA-induced seizure, suggest that Nurr1 expression is modulated by neuronal activity. On the other hand, prolonged Nurr1 induction in regions sensitive to KA toxicity indicates a possible involvement of Nurr1 in selective neuronal vulnerability.

Chemoprevention of lung cancer

CHEMOPREVENTION The chemoprevention of lung cancer is a major challenge for health care providers and researchers, but it also presents a significant opportunity for reducing lung cancer morbidity and mortality. Chemoprevention strategies can be applied to those at high risk, such as current or former smokers, and to those who have survived earlystage non-small cell lung cancer (NSCLC) but are at risk for second primary tumors. Many agents are being studied for chemopreventive activity. The most widely studied compounds are retinoids. These are a group of natural and synthetic vitamin A analogs that have been shown in animal models to suppress carcinogenesis and to affect the growth and differentiation of normal, premalignant, and malignant epithelial cells in vitro and in vivo. These agents work through a group of nuclear receptors that are part of the steroid and thyroid hormone receptor family. These receptors selectively regulate gene transcription, thereby regulating cell differentiation and proliferation. ~ Specific retinoid compounds studied in clinical trials include isotretinoin (13-cis-retinoic acid), etretinate, and retinol (retinyl palmitate). Their administration is associated with dose-related skin toxicity, which is reversible but often limits their use. In epidemiologic studies, dietary i~-carotene intake has been shown to be inversely correlated with lung cancer risk. 2 i~-Carotene is thought to function as an electron-scavenging antioxidant. 3 Vitamin E intake has also been associated with decreased incidence of cancer at several sites. 4 This vitamin also acts as an antioxidant. N-acetylcysteine is an aminothiol cysteine derivative and a precursor of glutathione. Glutathione plays a role in the detoxification of reactive electrophiles and free radicals through conjugation or reduction reactions. N-acetylcysteine has been shown in animal models to have preventive activity against many carcinogenic agents? Aspirin and other nonsteroidal antiinflammatory compounds are 266

RB phosphorylation in sodium butyrate-resistant HL-60 cells: cross-resistance to retinoic acid but not vitamin D3.

To examine the potential coupling between inducible cellular changes in RB (retinoblastoma) tumor suppressor protein phosphorylation and ability to G0 growth arrest and differentiate, HL-60 promyelocytic leukemia cells were cultured in incremental sodium butyrate (NaB) concentrations and thereby made resistant to the growth inhibitory effects of sodium butyrate, which normally induces G0 arrest and monocytic differentiation in wild type HL-60 cells. The resistant cells were also unable to differentiate in response to NaB, indicating that a regulatory function controlling both G0 growth arrest and differentiation had been affected. The induced resistance was not genetic in origin since the cells regained the ability to G0 arrest and differentiate after being recultured in medium free of sodium butyrate for only three days. The resistant cells had similar cell cycle phase durations as the original wild type cells. The resistant cells retained the ability to both G0 arrest and differentiate in response to 1,25-dihydroxy vitamin D3 (VD3), normally an inducer of G0 arrest and monocytic differentiation in wild type cells. However, they were cross-resistant to retinoic acid (RA), another ligand for the same steroid thyroid hormone receptor family, which induces G0 arrest and myeloid differentiation in wild type cells. The ability to G0 arrest and phenotypically differentiate in response to RA were both grossly impaired. Unlike wild type cells which undergo early down-regulation and then hypophosphorylation of the RB protein when induced to differentiate, in resistant cells, hypophosphorylation of RB in response to NaB was grossly retarded. These changes in RB protein occurred faster when the cells were treated with VD3. In contrast, the changes in RB phosphorylation occurred significantly slower when the cells were treated with RA. The results suggest a coupling between the ability to G0 growth arrest and phenotypically convert and the ability to hypophosphorylate RB.

Vertebrate receptors: molecular biology, dimerization and response elements

The nuclear receptors are a large family of ligand sensitive transcriptional regulators. They bind specific DNA sequences (response elements) in the promoter region of responsive genes. While the steroid hormone receptors bind as homodimers just two basic response elements, the retinoid and thyroid hormone receptor family interacts with a diverse set of response elements as homo- and heterodimers. The retinoid X receptors have a central role, since they form heterodimers with a whole subclass of receptors, consistent with the pleiotropic effects of retinoids. Differences in the mechanism of actions between steroid hormone receptors and other members of the family are discussed.