A5024656910- Thyroid Disorders and Treatments
- Supply Chain and Inventory Management
- Scheduling and Optimization Algorithms
- Genetics and Neurodevelopmental Disorders
- Retinoids in leukemia and cellular processes
- Ubiquitin and proteasome pathways
- Product Development and Customization
- Auction Theory and Applications
- Erythrocyte Function and Pathophysiology
- Cellular transport and secretion
- Growth Hormone and Insulin-like Growth Factors
- Regulation of Appetite and Obesity
- Endoplasmic Reticulum Stress and Disease
- Mitochondrial Function and Pathology
- Protein Tyrosine Phosphatases
- Business Strategy and Innovation
- Cholesterol and Lipid Metabolism
- Galectins and Cancer Biology
- Digital Platforms and Economics
- Resource-Constrained Project Scheduling
- Cytokine Signaling Pathways and Interactions
- Protein Kinase Regulation and GTPase Signaling
- Business Process Modeling and Analysis
- Vitamin D Research Studies
- Manufacturing Process and Optimization
Czech Academy of Sciences, Institute of Experimental Medicine
2023-2025
HUN-REN Institute of Experimental Medicine
2009-2023
Institute of Organic Chemistry
2020-2022
HUN-REN Research Centre for Natural Sciences
2022
Hungarian Academy of Sciences
2007-2018
Semmelweis University
2013-2016
Pázmány Péter Catholic University
2015
Erasmus University Rotterdam
2015
Erasmus MC
2015
Tufts Medical Center
2015
Hypothyroidism in humans is characterized by severe neurological consequences that are often irreversible, highlighting the critical role of thyroid hormone (TH) brain. Despite this, not much known about signaling pathways control TH action What prohormone thyroxine (T4) converted to active triiodothyronine (T3) type 2 deiodinase (D2) and this occurs astrocytes, while receptors 3 (D3), which inactivates T3, found adjacent neurons. Here, we modeled brain using an vitro coculture system...
Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 converted active T3 by type 2 deiodinase (D2). Thus, it intriguing that carriers Thr92Ala polymorphism in D2 gene (DIO2) exhibit clinical improvement when liothyronine (LT3) added LT4 therapy. Here, we report cargo protein ER Golgi intermediary compartment (ERGIC) vesicles, recycling between and Golgi. The Thr92-to-Ala substitution (Ala92-D2) caused stress activated unfolded response (UPR)....
A common polymorphism in the gene encoding activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life millions patients hypothyroidism and several organ-specific conditions. This results a single amino acid change within D2 molecule where its susceptibility ubiquitination proteasomal degradation regulated.To define molecular mechanisms underlying conditions carriers Thr92Ala-D2 polymorphism.Microarray analyses 19 postmortem human cerebral cortex samples were performed...
Few studies have included subjects with the propensity to reach old age in good health, aim disentangle mechanisms contributing staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and (TH) an inverse relationship. Greater longevity has been associated higher TSH lower TH levels, but underlying TSH/TH differences remain unknown. HPT plays a pivotal role growth, development energy metabolism. We report...
The endoplasmic reticulum resident thyroid hormone-activating type 2 deiodinase (D2) is inactivated by ubiquitination via the hedgehog-inducible WSB-1. Ubiquitinated D2 can then be subsequently taken up proteasomal system or reactivated USP-33/20-mediated deubiquitination. Given that heterologously expressed accumulates in Saccharomyces cerevisiae lacking E3 ligase Doa10, we tested whether human Doa10 ortholog, TEB4, plays a role and degradation. In setting of transient coexpression HEK-293...
Abstract Transcription factor phosphorylation at specific sites often activates gene expression, but how environmental cues quantitatively control transcription is not well-understood. Activating protein 1 factors are phosphorylated by mitogen-activated kinases (MAPK) in their transactivation domains (TAD) so-called phosphoswitches, which a hallmark response to growth factors, cytokines or stress. We show that the ATF2 TAD controlled functionally distinct signaling pathways (JNK and p38)...
L-thyroxine (L-T4) monotherapy is the standard treatment for hypothyroidism, administered daily to normalize TSH levels. Once absorbed, T4 converted T3 alleviate most symptoms. However, this abnormally elevates plasma levels in over 50% of patients. Using L-T4-treated Thyroid Hormone (TH) Action Indicator mice, which express a T3-regulated luciferase (Luc) reporter, we examined whether these elevations disrupt TH signaling. Hypothyroid mice exhibited reduced Luc expression across brain...
The development of the brain, as well mood and cognitive functions, are affected by thyroid hormone (TH) signaling. Neurons critical cellular target for TH action, with T3 regulating expression important neuronal gene sets. However, steps involved in signaling remain poorly known given that neurons express high levels type 3 deiodinase (D3), which inactivates both T4 T3. To investigate this mechanism, we used a compartmentalized microfluid device identified novel pathway transport action...
Thyroid hormone receptor (TR) and liver X-receptor (LXR) are the master regulators of lipid metabolism. Remarkably, a mouse with targeted deletion both LXR alpha beta is resistant to western diet-induced obesity, exhibits ectopic expression thyroid activating type 2 deiodinase (D2). We hypothesized that LXR/retinoid (RXR) signaling inhibits hepatic D2 expression, studied this using luciferase reporter containing human DIO2 (hDIO2) promoter in HepG2 cells. Given that, contrast mammals,...
Interleukin (IL)‐6 deficient mice develop mature‐onset obesity. Furthermore, i.c.v. administration of IL‐6 increases energy expenditure, suggesting that centrally regulates homeostasis. To investigate whether it would be possible for to directly influence the homeostasis via hypothalamic regulation in humans and rodents, we mapped distribution ligand binding receptor α (IL‐6Rα) this brain region. In human hypothalamus, IL‐6Rα‐immunoreactivity was detected perikarya first‐order dendrites...
The hypothalamic activation of thyroid hormones by type 2 deiodinase (D2), catalyzing the conversion thyroxine to T3, is critical for proper function hypothalamo-pituitary-thyroid (HPT) axis. Regulation D2 expression in tanycytes alters activity HPT However, signals that regulate are poorly understood. pituitary adenylate cyclase-activating polypeptide (PACAP) increases intracellular cAMP level, a second messenger known stimulate DIO2 gene; however, its importance not completely...
The type II iodothyronine deiodinase (D2) is a I endoplasmic reticulum (ER)-resident thioredoxin fold-containing selenoprotein that activates thyroid hormone. D2 inactivated by ER-associated ubiquitination and can be reactivated two ubiquitin-specific peptidase-class D2-interacting deubiquitinases (DUBs). Here, we used D2-expressing cell models to define (UbD2) occurs via K48-linked ubiquitin chains exposure its natural substrate, T4, accelerates UbD2 formation retrotranslocation the...
Activation of thyroxine by outer ring deiodination is the crucial first step thyroid hormone action. Substrate-induced ubiquitination type 2 deiodinase (D2) most rapid and sensitive mechanism known to regulate activation. While molecular machinery responsible for D2 has been extensively studied, combination features sufficient required allow have not previously determined. To address this question, we constructed chimeric deiodinases introducing different combinations D2-specific elements...
Abstract Serine/threonine phosphorylation of insulin receptor substrate (IRS) proteins is well known to modulate signaling. However, the molecular details this process have mostly been elusive. While exploring role phosphoserines, we detected a direct link between Tyr-flanking Ser/Thr sites and regulation specific phosphotyrosine phosphatases. Here present concise structural study on how activity SHP2 phosphatase controlled by an asymmetric, dual its substrates. The structure has determined...
Background: The firefly luciferase reporter protein is a crucial tool for studies targeting broad range of biological questions. Importantly, assays are also widely used to explore mechanisms underlying thyroid hormone dependent regulation gene expression. However, it was demonstrated that the subject triiodothyronine (T3)-evoked, promoter independent downregulation mediated by receptor. Since this effect can interfere with readout accuracy, study aimed find reporters not susceptible...
Abstract The effectiveness of therapy for hypothyroidism with levothyroxine (L-T4) depends on patients’ ability to activate T4 T3 —altered in carriers a common deiodinase polymorphism (Thr92Ala-DIO2). Some patients that exhibit impaired mood and cognition improve liothyronine (L-T3), but the underlying mechanisms remain unknown. Here we show T3-indicator mouse carrying Thr92Ala-DIO2 exhibits hippocampal-specific reduction activation signaling limits L-T4 therapy. To understand L-T3 effect,...
The paper defines generic requirements towards cooperative planning in the nucleus of any supply network that is constituted by a pair autonomous manufacturer and supplier who possess asymmetric information on demand forecast costs, respectively. Then novel way suggested for investigating this problem means apparatus mechanism design. analysis results some provable properties as efficiency truthfulness, shows impossibility fair cost profit sharing. Further on, design principles payment...