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Introduction
Publications
Publications (83)
Aim: To study the expression of histone methyltransferase SMYD1 in white adipose tissue (WAT) and brown adipose tissue and during differentiation of preadipocytes to white and beige phenotypes. Methods: C57BL/6J mice fed a high-fat diet (and exposed to cold) and 3T3-L1 cells stimulated to differentiate into white and beige adipocytes were used. Res...
Peripheral nerve injuries lead to severe functional impairments and long recovery times, with limited effectiveness and accessibility of current treatments. This has increased interest in natural bioactive compounds, such as ursolic acid (UA). Our study evaluated the effect of an oleolyte rich in UA from white grape pomace (WGPO) on neuronal regene...
Sirtuin 6 (SIRT6) has a critical role in cutaneous Squamous Cell Carcinoma (cSCC): SIRT6 silencing in skin SCC cells has pro-differentiating effects and SIRT6 deletion abrogated DMBA-TPA-induced skin tumorigenesis in mice. On the other hand, SIRT6 acts as tumor suppressor in SCC by enhancing glycolysis in tumor propagating cells. Herein, pharmacolo...
Skeletal muscle (SkM) lipid composition plays an essential role in physiological muscle maintenance and exercise performance. Thyroid hormones (THs) regulate muscle formation and fuel energy utilization by modulating carbohydrates and lipid and protein metabolism. The best-known effects of THs in SkM include the promotion of mitochondrial biogenesi...
The Thyroid Hormone (TH) activating enzyme, type 2 Deiodinase (D2), is functionally required to elevate the TH concentration during cancer progression to advanced stages. However, the mechanisms regulating D2 expression in cancer still remain poorly understood. Here, we show that the cell stress sensor and tumor suppressor p53 silences D2 expressio...
The circadian rhythm is regulated by an intrinsic time-tracking system, composed both of a central and a peripheral clock, which influences the cycles of activities and sleep of an individual over 24hours. At the molecular level, the circadian rhythm begins when two basic helix-loop-helix/Per-ARNT-SIM (bHLH-PAS) proteins, BMAL-1 and CLOCK, interact...
There is increasing evidence that thyroid hormones (THs) work in an integrative fashion with androgen receptors (ARs) to regulate gonadal differentiation and reproductive function. Studies reveal that THs have interactions with the AR promoter region and increase AR expression. THs also have a role in the regulation of enzymes involved in the biosy...
Chronic hemodynamic overload of the heart induces ventricular hypertrophy that may be either compensatory or progress to decompensation and heart failure. The gradual impairment of ventricular function is, at least in part, the result of a reduction of cardiac thyroid-hormone (TH) action. Here, we examined the proposed roles of increased cardiac ex...
The iodothyronine deiodinases constitute a family of three selenoenzymes regulating the intracellular metabolism of Thyroid Hormones (THs, T4 and T3) and impacting on several physiological processes, including energy metabolism, development and cell differentiation. The type 1, 2 and 3 deiodinases (D1, D2, and D3), are sensitive, rate-limiting comp...
Treatment with tyrosine kinase inhibitors has been associated with alterations in circulating thyroid hormone levels, possibly related to perturbations in peripheral thyroid hormone metabolism. In this study, we evaluated the effect of the multi-kinase inhibitor vandetanib on the expression of the three deiodinase selenoenzymes, responsible for the...
Ischemic stroke is one of the leading global causes of neurological morbidity and decease. Its etiology depends on multiple events such as cardiac embolism, brain capillaries occlusion and atherosclerosis, which ultimately culminate in blood flow interruption, incurring hypoxia and nutrient deprivation. Thyroid hormones (THs) are pleiotropic modula...
Skeletal muscle is a key energy-regulating organ, skilled in rapidly boosting the rate of energy production and substrate consumption following increased workload demand. The alteration of skeletal muscle metabolism is directly associated with numerous pathologies and disorders. Thyroid hormones (THs) and their receptors (TRs, namely, TRα and TRβ)...
Thyroid hormones (THs) are key metabolic regulators coordinating short- and long-term energy needs. In skeletal muscle, THs modulate energy metabolism in pathophysiological conditions. Indeed, hypo- and hy- perthyroidism are leading causes of muscle weakness and strength; however, the metabolic pathways un- derlying these effects are still poorly u...
Thyroid hormones (THs) are key metabolic regulators coordinating short- and long-term energy needs. In skeletal muscle, THs modulate energy metabolism in pathophysiological conditions. Indeed, hypo- and hyperthyroidism are leading causes of muscle weakness and strength; however, the metabolic pathways underlying these effects are still poorly under...
Prostate Cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in males and the fifth leading cause of death worldwide. The majority of PCas are androgen-sensitive, with a significant up-regulation of Androgen Receptor (AR) that causes a stimulatory effect on growth and progression of cancer cells. For this reason, the first-line therapy...
Stem cells are critical for the regeneration and homeostasis of adult tissues. Thyroid hormone (TH), whose intracellular concentration is increased by Type 2 deiodinases (D2), is implicated in multiple cell functions. While reduced TH levels play a role in muscle stem cell activation, nothing in known about the role of TH in quiescence. Here we sho...
Thyroid hormones (THs) are key regulators of different biological processes. Their action involves genomic and non-genomic mechanisms, which together mediate the final effects of TH in target tissues. However, the proportion of the two processes and their contribution to the TH-mediated effects are still poorly understood. Skeletal muscle is a clas...
Simple Summary
Cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance. Aerobic glycolysis is a prominent trait of many cancers; contextually, glutamine addiction, enhanced glucose uptake and aerobic glycolysis sustain the metabolic needs of rapidly proliferating cancer cells. Thyroid hormone (TH)...
Melanoma is the most lethal form of skin cancer and its incidence is growing worldwide. In the last ten years, the therapeutic scenario of this disease has been revolutionized by the introduction of targeted therapies and immune-checkpoint inhibitors. However, in patients with many lesions and bulky tumors, in which surgery is no longer feasible, t...
Thyroid hormones (THs) are key endocrine regulators of tissue development and homeostasis. They are constantly released into the bloodstream and help to regulate many cell functions. The principal products released by the follicular epithelial cells are T3 and T4. T4, which is the less active form of TH, is produced in greater amounts than T3, whic...
Hormones are key drivers of cancer development, and alteration of the intratumoral concentration of thyroid hormone (TH) is a common feature of many human neoplasias. Besides the systemic control of TH levels, the expression and activity of deiodinases constitute a major mechanism for the cell-autonomous, pre-receptoral control of TH action. The ac...
Background:
Many physiological effects of thyroid hormone (TH) are mediated by its canonical action via nuclear receptors (TH receptor α and β [TRα and TRβ]) to regulate transcription of target genes. Heterozygous dominant negative mutations in human TRα mediate resistance to thyroid hormone alpha (RTHα), characterized by features of hypothyroidism...
Background
RAS mutations are the only validated biomarkers in metastatic colorectal cancer (mCRC) for anti-epidermal growth factor receptor (EGFR) therapy. Limited clinical information is available on AXL expression, marker of epithelial to mesenchymal transition, in mCRC.
Methods
AXL was retrospectively assessed by immunohistochemistry in 307 pat...
Background:
The type 2 deiodinase (DIO2) converts thyroxine (T4) to 3,3',5-triiodothyronine (T3), modulating intracellular T3. An increase in DIO2 within muscle stem cells during skeletal muscle regeneration leads to T3-dependent potentiation of differentiation. The muscle stem cell niche is comprised of numerous cell types, which coordinate the r...
Liver diseases affect millions of people worldwide. In most of the cases, severe hepatic dysfunction and liver cancer stem from mild and common clinical signs including hepatic steatosis, insulin resistance, liver inflammation, and oxidative stress, all together referred to as Nonalcoholic Fatty Liver Disease (NAFLD). Nutraceuticals endowed with an...
Type 2 deiodinase (D2), the principal activator of thyroid hormone (TH) signaling in target tissues, is expressed in cutaneous squamous cell carcinomas (SCCs) during late tumorigenesis, and its repression attenuates the invasiveness and metastatic spread of SCC. Although D2 plays multiple roles in cancer progression, nothing is known about the mech...
Background:
Thyroid hormones (THs) are key regulators of development, tissue differentiation, and maintenance of metabolic balance in virtually every cell of the body. Accordingly, severe alteration of TH action during fetal life leads to permanent deficits in humans. The skin is among the few adult tissues expressing the oncofetal protein type 3 d...
Thyroid hormone action defects (THADs) have been classically considered conditions of impaired sensitivity to thyroid hormone (TH). They were originally referring to alterations in TH receptor genes (THRA and THRB), but the discovery of genetic mutations and polymorphisms causing alterations in cell membrane transport (e.g., MCT8) and metabolism (e...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Epithelial tumor progression often involves epithelial-mesenchymal transition (EMT). We report that increased intracellular levels of thyroid hormone (TH) promote the EMT and malignant evolution of squamous cell carcinoma (SCC) cells. TH induces the EMT by transcriptionally up-regulating ZEB-1, mesenchymal genes and metalloproteases and suppresses...
The deiodinase family of enzymes mediates the activation and inactivation of thyroid hormone. The role of these enzymes in the regulation of the systemic concentrations of thyroid hormone is well established and underpins the treatment of common thyroid diseases. Interest in this field has increased in the past 10 years as the deiodinases became im...
Thyroid hormone (TH) is a key metabolic regulator that acts by coordinating short- and long-term energy needs. Accordingly, significant metabolic changes are observed depending on thyroid status. Although it is established that hyperthyroidism augments basal energy consumption, thus resulting in an enhanced metabolic state, the net effects on cellu...
The type 2 iodothyronine-deiodinase (D2) enzyme converts T4 to T3, and mice deficient in this enzyme (D2KO mice) have decreased T3 derived from T4 in skeletal muscle despite normal circulating T3 levels. Because slow skeletal muscle is particularly susceptible to changes in T3 levels, we expected that D2 inactivation would result in more pronounced...
Recently the attention of the scientific community has focused on the ability of polyphenols to counteract adverse epigenetic regulation involved in the development of complex conditions such as obesity. The aim of this study was to investigate the epigenetic mechanisms underlying the anti-adiposity effect of Quercetin (3,3′,4′,5,7-pentahydroxyflav...
Proliferation of pancreatic acinar cells is a critical process in the pathophysiology of pancreatic diseases, because limited or defective proliferation is associated with organ dysfunction and patient morbidity. In this context, elucidating the signalling pathways that trigger and sustain acinar proliferation is pivotal to develop therapeutic inte...
Reduction in cholesterol blood levels represents one of the therapeutic goals to achieve in order to reduce the occurrence of cardiovascular diseases. Commonly, this goal is attempted by promoting healthy lifestyle behaviors and low-fat diets. Recently, several nutraceuticals have been shown to possess cholesterol-lowering properties and are becomi...
Canonical thyroid hormone (TH) signaling results from the interaction of T3 with nuclear receptors and stimulation or repression target genes. Ligand (T3) availability is under tight control of several intracellular checkpoints, which enable target cells to modify their own T3 fingerprint. A crucial step of intracellular T3 metabolism is catalyzed...
Chemotherapy-induced alopecia (CIA) is a common side effect of conventional chemotherapy and represents a major problem in clinical oncology. Even months after the end of chemotherapy, many cancer patients complain of hair loss, a condition that is psychologically difficult to manage. CIA disturbs social and sexual interactions and causes anxiety a...
Patterned hair loss (PHL) affects around 50% of the adult population worldwide.
The negative impact that this condition exerts on people’s life quality has boosted the appearance of over-the-counter products endowed with hair-promoting activity. Nutraceuticals enriched in polyphenols have been recently shown to promote hair growth and counteract PH...
Thyroid hormones (THs) are key determinants of cellular metabolism and regulate a variety of pathways that are involved in the metabolism of carbohydrates, lipids and proteins in several target tissues. Notably, hyperthyroidism induces a hyper-metabolic state characterized by increased resting energy expenditure, reduced cholesterol levels, increas...
Interest in thyroid hormone (TH) in cancer was first aroused by the demonstration, over a century ago, that breast cancer responded to thyroid extract treatment. This suggested that TH was a key regulator of tumorigenesis. However, the role of TH in the complex process of neoplastic transformation long remained obscure. Interest in the link between...
Tumor formation and maintenance depend on a small fraction of cancer stem cells (CSCs) that can self-renew and generate a wide variety of differentiated cells. CSCs are resistant to chemotherapy and radiation, and can represent a reservoir of cancer cells that often cause relapse after treatment. Evidence suggests that CSCs also give rise to metast...
Context:
A significant proportion of athyreotic LT4-treated patients experience hypothyroid-like symptoms. During LT4 replacement, levels of the active hormone triiodothyronine (T3) strictly depend on type-2-deiodinase (D2)-mediated activation of LT4. The Thr92Ala polymorphism and the 258 G/A in the DIO2 gene have been associated with various clin...
Background:
Thyroid hormones (THs) mediate pleiotropic cellular processes involved in metabolism, cellular proliferation and differentiation. The intracellular hormonal environment can be tailored by the deiodinase enzymes, D2 and D3, which catalyze TH activation and inactivation, respectively. In many cellular systems, THs exert well documented s...
Neutrophils are important effector cells of the innate immune system. Thyroid hormone is thought to play an important role in their function. Intracellular thyroid hormone levels are regulated by the deiodinating enzymes. The thyroid hormone inactivating type 3 deiodinase (D3) is expressed in infiltrating murine neutrophils and D3 knockout mice sho...
The thyroid hormone-inactivating (TH-inactivating) enzyme type 3 iodothyronine deiodinase (D3) is an oncofetal protein that is rarely expressed in adult life but has been shown to be reactivated in the context of proliferation and neoplasms. D3 terminates TH action within the tumor microenvironment, thereby enhancing cancer cell proliferation. Howe...
Thyroid hormone (TH) is a pleiotropic factor that controls many cellular processes in multiple cell types such as cancer stem cells (CSCs). TH concentrations in the blood are stable, but the action of the deiodinases (D2-D3) provides cell-specific regulation of TH activity. Deregulation of deiodinase function and TH status has been implicated in tu...
Precise control of the thyroid hormone (T3)-dependent transcriptional program is required by multiple cell systems, including muscle stem cells. Deciphering how this is achieved and how the T3 signal is controlled in stem cell niches is essentially unknown. We report that in response to proliferative stimuli such as acute skeletal muscle injury, ty...
The type 2 deiodinase (D2) is essential for feedback regulation of TSH by thyroxine (T4). We genetically inactivated in vivo D2 in thyrotrophs using a mouse model of Cga-driven cre recombinase. Pituitary D2 activity was reduced 90% in the Cga-cre D2KO mice compared with control Dio2(fl/fl) mice. There was no growth or reproductive phenotype. Basal...
Il controllo della funzione tiroidea è affidato principalmente a tre sistemi di regolazione: il primo è costituito dalla liberazione ipofisaria di TSH (a sua volta controllata dalla liberazione ipotalamica di TRH con un meccanismo a feedback); il secondo, intratiroideo, consiste nella possibilità di autoregolazione della liberazione di T3 e T4 in f...
Type 3 deiodinase (D3), the physiologic inactivator of thyroid hormones, is induced during tissue injury and regeneration. This has led to the hypotheses that D3 impacts injury tolerance by reducing local T3 signaling and contributes to the fall in serum triiodothyronine (T3) observed in up to 75 of sick patients (termed the low T3 syndrome). Here...
Thyroid hormone (TH) is an important regulator of growth, development and metabolism. Most of the active thyroid hormone (TH) T3 is generated by peripheral TH metabolism mediated by the iodothyronine deiodinases. Type 3 deiodinase (D3) inactivates T3 via specific deiodination reactions. It is an oncofetal protein frequently expressed in neoplastic...
Thyroid hormone signalling regulates crucial biological functions, including energy expenditure, thermogenesis, development and growth. The skeletal muscle is a major target of thyroid hormone signalling. The type 2 and 3 iodothyronine deiodinases (DIO2 and DIO3, respectively) have been identified in skeletal muscle. DIO2 expression is tightly regu...
Introduction:
Thyroid hormone (TH) metabolism is mediated by deiodinases, a family of thioredoxin fold-containing enzymes that remove iodide from thyroxine and its derivatives. The coordinated action of deiodinases allows target cells to modulate rapidly their own TH availability in response to different cues. Type 3 deiodinase (D3), the physiolog...
Skin is the largest organ of the human body and plays a key role in protecting the individual from external insults. The barrier function of the skin is performed primarily by the epidermis, a self-renewing stratified squamous epithelium composed of cells that undergo a well-characterized and finely tuned process of terminal differentiation. By bin...
The proliferation and differentiation of muscle precursor cells require myogenic regulatory factors and chromatin modifiers
whose concerted action dynamically regulates access to DNA and allows reprogramming of cells towards terminal differentiation.
Type 2 deiodinase (D2), the thyroid hormone (TH)-activating enzyme, is sharply upregulated during m...
Thyroid hormone (TH) is a pleiotropic agent that has widespread biological functions, i.e., it controls cellular growth, tissue development and homeostasis and neoplastic transformation. Suitable TH levels are critical for the development of various types of tissues and are essential for the regulation of metabolic processes throughout life. The se...
Activation of the β-catenin/T-cell factor (TCF) complex occurs in most colon tumors, and its actions correlate with the neoplastic phenotype of intestinal epithelial cells. Type 3 deiodinase (D3), the selenoenzyme that inactivates thyroid hormone (3,5,3' triiodothyronine [T3]), is frequently expressed by tumor cells, but little is known about its r...
Background
Thyroid hormone influences gene expression in virtually all vertebrates. Its action is initiated by the activation of T4 to T3, an outer ring deiodination reaction that is catalyzed by the type 1 or the type 2 iodothyronine selenodeiodinases (D1 or D2). Inactivation of T4 and T3 occurs via inner ring deiodination catalyzed by the type 3...
The FoxO3-dependent increase in type II deiodinase (D2), which converts the prohormone thyroxine (T(4)) to 3,5,3'-triiodothyronine (T(3)), is required for normal mouse skeletal muscle differentiation and regeneration. This implies a requirement for an increase in D2-generated intracellular T(3) under these conditions, which has not been directly de...
Deiodination is a critical process by which the minimally active thyroxine (T(4)) molecule is converted into the favorite ligand for thyroid hormone (TH) receptors, triiodothyronine (T(3)). The iodothyronine deiodinases type 1, 2, and 3 (D1, D2, and D3) constitute a potent mechanism of TH activation (D1 and D2) or inactivation (D3), which functions...
Introduction:
The three iodothyronine deiodinases catalyze the metabolic pathway that removes one iodine residue from the T4 molecule, thus producing either the active T3 or the inactive metabolite rT3. Hence, deiodination is a potent mechanism by which to modulate thyroid hormone (TH) action at cellular level, thereby allowing cells to customize...
The active thyroid hormone 3,5,3' triiodothyronine (T3) is a major regulator of skeletal muscle function. The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4). Here we show that type 2 deiodinase (D2) is essential for normal mouse myogenesis and muscle regeneration. Indeed, D2-me...
Because of its large mass, relatively high metabolic activity and responsiveness to thyroid hormone, skeletal muscle contributes significantly to energy expenditure. Despite the presence of mRNA encoding the type 2 iodothyronine-deiodinase (D2), an enzyme that activates T(4) to T3, very low or undetectable activity has been reported in muscle homog...
The pro-hormone, thyroxine (T4), must be converted into T3 in order to be active. This metabolic process has been increasingly recognized as an essential mechanism that regulates thyroid hormone (TH) action at cellular level. TH action is regulated by the activity of the deiodinases, which can either activate (D1, D2) or inactivate (D3) the prohorm...
Thyroid hormone (TH) influences a wide variety of biological events in vertebrates. Among them, the balance between proliferation and differentiation is crucial in TH action in normal and pathological conditions, including cancer. Thyroid hormone signaling results from the interaction of T3 with nuclear receptors that, in concert with other transcr...
p63 and p73 are highly homologous members of the p53 family that originated by gene duplication at the invertebrate-to-vertebrate transition. We characterize here a previously unreported gene, Transformation-related protein 63 regulated (Tprg), located upstream of the p63 gene in the vertebrate genome, with striking similarity to Transformation rel...
The thyroid hormone plays a fundamental role in the development, growth, and metabolic homeostasis in all vertebrates by affecting the expression of different sets of genes. A group of thioredoxin fold-containing selenoproteins known as deiodinases control thyroid hormone action by activating or inactivating the precursor molecule thyroxine that is...
The Sonic hedgehog (Shh) pathway plays a critical role in hair follicle physiology and is constitutively active in basal cell carcinomas (BCCs), the most common human malignancy. Type 3 iodothyronine deiodinase (D3), the thyroid hormone-inactivating enzyme, is frequently expressed in proliferating and neoplastic cells, but its role in this context...
Ubiquitination is a critical posttranslational regulator of protein stability and/or subcellular localization. Here we show
that ubiquitination can also regulate proteins by transiently inactivating enzymatic function through conformational change
in a dimeric enzyme, which can be reversed upon deubiquitination. Our model system is the thyroid horm...
Thyroid hormone activation is catalyzed by two deiodinases, D1 and D2. Whereas D1 is a stable plasma membrane protein, D2 is resident in the endoplasmic reticulum (ER) and has a 20-min half-life due to selective ubiquitination and proteasomal degradation. Here we have shown that stable retention explains D2 residency in the ER, a mechanism that is...
Thyroid hormone activation is catalyzed by two deiodinases, D1 and D2. Whereas D1 is a stable plasma membrane protein, D2 is resident in the endoplasmic reticulum (ER) and has a 20-min half-life due to selective ubiquitination and proteasomal degradation. Here we have shown that stable retention explains D2 residency in the ER, a mechanism that is...
Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000-4000 at birth. In 80-85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located, and/or severely reduced gland [thyroid dysgenesis (TD)]. Mutations in genes controlling thyroid development have demonstrated that in...
Thyroid transcription factor gene 1 (TTF-1) is a homeobox-containing gene involved in thyroid organogenesis. During early thyroid development, the homeobox gene Nkx-2.5 is expressed in thyroid precursor cells coincident with the appearance of TTF-1. The aim of this study was to investigate the molecular mechanisms underlying thyroid-specific gene e...
WSB-1 is a SOCS-box-containing WD-40 protein of unknown function that is induced by Hedgehog signalling in embryonic structures during chicken development. Here we show that WSB-1 is part of an E3 ubiquitin ligase for the thyroid-hormone-activating type 2 iodothyronine deiodinase (D2). The WD-40 propeller of WSB-1 recognizes an 18-amino-acid loop i...
The sodium/iodide symporter (NIS) is a plasma membrane protein that mediates active iodide transport in thyroid and mammary
cells. It is a prerequisite for radioiodide treatment of thyroid cancer and a promising diagnostic and therapeutic tool for
breast cancer. We investigated the molecular mechanisms governing NIS expression in mammary cells. Her...
The type 2 iodothyronine selenodeiodinase (D2) is an endoplasmic reticulum (ER)-resident selenoprotein that activates T4 to T3, playing a critical role in thyroid homeostasis. D2 has an approximately 45-min half-life due to selective ubiquitin-mediated ER-associated degradation (ERAD), a process of particular interest because it is accelerated by e...
By producing T3 from T4, type 2 iodothyronine deiodinase (D2) catalyzes the first step in the cascade underlying the effect exerted by thyroid hormone. Type 2 iodothyronine deiodinase mRNA is expressed at high levels in human heart but is barely detectable in the corresponding rodent tissue. Although the heart is a major target of thyroid hormone,...
