NFE2-Related Transcription Factor 2 Coordinates Antioxidant Defense with Thyroglobulin Production and Iodination in the Thyroid Gland

Ziros, Panos G.; Habeos, Ioannis; Chartoumpekis, Dionysios V.; Ntalampyra, Eleni; Somm, Emmanuel; Renaud, Cédric O; Bongiovanni, Massimo; Trougakos, Ioannis P.; Yamamoto, Masayuki; Kensler, Thomas W.; Santisteban, Pilar; Carrasco, Nancy; Ris‐Stalpers, Carrie; Amendola, Elena; Liao, Xiao Hui; Rossich, Luciano; Thomasz, Lisa; Juvenal, Guillermo; Refetoff, Samuel; Sykiotis, Gerasimos P.

doi:10.1089/thy.2018.0018

Cited by 30 publications

(107 citation statements)

References 82 publications

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“…Accumulation of p62 and LC3b in Vps34 cKO indicates a block in the autophagy process. In addition, p62 accumulation suggests activation of the antioxidant NRF2 pathway by competitive binding of p62 to KEAP1 (33,43). We indeed observed increased expression of two NRF2 target genes, namely the quinone reductase, Nqo1, and the thioredoxin reductase 1, Txnrd1.…”

Section: Discussionsupporting

confidence: 52%

“…As the LAMP-1 signal was increased in Vps34 cKO , these p62/LC3-positive punctae sometimes colocalized with LAMP-1. We conclude that LC3 could be recruited on p62 aggregates but that progression to autophagosome maturation Recent evidence has demonstrated that p62 is also an activator of the antioxidant KEAP1/NRF2 pathway, which impacts thyrocyte physiology and Tg biology (33). We thus examined the possibility that stabilized p62 would compete with NRF2 for KEAP1 binding in Vps34 cKO , thus allowing NRF2 to reach the nucleus and activate gene expression.…”

Section: Evaluation Of Autophagy In Vps34 Cko Thyroidmentioning

confidence: 96%

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Class III PI3K Vps34 Controls Thyroid Hormone Production by Regulating Thyroglobulin Iodination, Lysosomal Proteolysis, and Tissue Homeostasis

Grieco

Wang

Delcorte

et al. 2020

Thyroid

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Background: The production of thyroid hormones [triiodothyronine (T3), thyroxine (T4)] depends on the organization of the thyroid in follicles, which are lined by a monolayer of thyrocytes with strict apicobasal polarity. This polarization supports vectorial transport of thyroglobulin (Tg) for storage into, and recapture from, the colloid. It also allows selective addressing of channels, transporters, ion pumps, and enzymes to their appropriate basolateral [Na + /Isymporter (NIS), SLC26A7, and Na + /K + -ATPase] or apical membrane domain (anoctamin, SLC26A4, DUOX2, DUOXA2, and thyroperoxidase). How these actors of T3/T4 synthesis reach their final destination remains poorly understood. The PI 3-kinase isoform Vps34/PIK3C3 is now recognized as a main component in the general control of vesicular trafficking and of cell homeostasis through the regulation of endosomal trafficking and autophagy. We recently reported that conditional Vps34 inactivation in proximal tubular cells in the kidney prevents normal addressing of apical membrane proteins and causes abortive macroautophagy. Methods: Vps34 was inactivated using a Pax8-driven Cre recombinase system. The impact of Vps34 inactivation in thyrocytes was analyzed by histological, immunolocalization, and messenger RNA expression profiling. Thyroid hormone synthesis was assayed by 125 I injection and plasma analysis. Results: Vps34 conditional knockout (Vps34 cKO ) mice were born at the expected Mendelian ratio and showed normal growth until postnatal day 14 (P14), then stopped growing and died at *1 month of age. We therefore analyzed thyroid Vps34 cKO at P14. We found that loss of Vps34 in thyrocytes causes (i) disorganization of thyroid parenchyma, with abnormal thyrocyte and follicular shape and reduced PAS + colloidal spaces; (ii) severe noncompensated hypothyroidism with extremely low T4 levels (0.75 -0.62 lg/dL) and huge thyrotropin plasma levels (19,300 -10,500 mU/L); (iii) impaired 125 I organification at comparable uptake and frequent occurrence of follicles with luminal Tg but nondetectable T4-bearing Tg; (iv) intense signal in thyrocytes for the lysosomal membrane marker, LAMP-1, as well as Tg and the autophagy marker, p62, indicating defective lysosomal proteolysis; and (v) presence of macrophages in the colloidal space. Conclusions: We conclude that Vps34 is crucial for thyroid hormonogenesis, at least by controlling epithelial organization, Tg iodination as well as proteolytic T3/T4 excision in lysosomes.

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Section: Discussionsupporting

confidence: 52%

Section: Evaluation Of Autophagy In Vps34 Cko Thyroidmentioning

confidence: 96%

Class III PI3K Vps34 Controls Thyroid Hormone Production by Regulating Thyroglobulin Iodination, Lysosomal Proteolysis, and Tissue Homeostasis

Grieco

Wang

Delcorte

et al. 2020

Thyroid

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“…Yet, in comparison to other tissues, relatively little is known about the role of proteostatic and antioxidant systems in the thyroid [24]. While a minimal amount of oxidative load is necessary in order for thyrocytes to proliferate and function normally [40,41], intrathyroidal oxidative stress occurs during pathological conditions like goitrogenesis or iodine deficiency, and this in turn activates the thyroid's antioxidant defenses [42][43][44][45].…”

Section: Role Of Nrf2 In the Thyroidal Antioxidant Responsementioning

confidence: 99%

“…Recent work has shown that Nrf2 signaling has a central role in the antioxidant response of the thyroid gland [43]. Nrf2 regulates the expression levels of genes like thioredoxin reductase 1 and glutathione peroxidase 2 [43], which are known to maintain homeostasis in thyroid cells by ameliorating oxidative insults [46,47]. In addition, Nrf2 protects the thyroid from oxidative damage induced by iodide overload [43].…”

Section: Role Of Nrf2 In the Thyroidal Antioxidant Responsementioning

confidence: 99%

“…Nrf2 regulates the expression levels of genes like thioredoxin reductase 1 and glutathione peroxidase 2 [43], which are known to maintain homeostasis in thyroid cells by ameliorating oxidative insults [46,47]. In addition, Nrf2 protects the thyroid from oxidative damage induced by iodide overload [43]. Importantly, Nrf2 coordinates antioxidant defense in the thyroid gland with Tg production and iodination, and it can actually regulate the transcription of the gene encoding Tg by binding to two ARE sequences in a conserved enhancer [43].…”

Section: Role Of Nrf2 In the Thyroidal Antioxidant Responsementioning

confidence: 99%

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Impact of Antioxidant Natural Compounds on the Thyroid Gland and Implication of the Keap1/Nrf2 Signaling Pathway

Paunkov

Chartoumpekis

Ziros

et al. 2019

CPD

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Background: Natural compounds with potential antioxidant properties have been used in the form of food supplements or extracts with the intent to prevent or treat various diseases. Many of these compounds can activate the cytoprotective Nrf2 pathway. Besides, some of them are known to impact the thyroid gland, often with potential side-effects, but in other instances, with potential utility in the treatment of thyroid disorders. Objective: In view of recent data regarding the multiple roles of Nrf2 in the thyroid, this review summarizes the current bibliography on natural compounds that can have an effect on thyroid gland physiology and pathophysiology, and it discusses the potential implication of the Nrf2 system in the respective mechanisms. Method & Results: Literature searches for articles from 1950 to 2018 were performed in PubMed and Google Scholar using relevant keywords about phytochemicals, Nrf2 and thyroid. Natural substances were categorized into phenolic compounds, sulfur-containing compounds, quinones, terpenoids, or under the general category of plant extracts. For individual compounds in each category, respective data were summarized, as derived from in vitro (cell lines), preclinical (animal models) and clinical studies. The main emerging themes were as follows: phenolic compounds often showed potential to affect the production of thyroid hormones; sulfur-containing compounds impacted the pathogenesis of goiter and the proliferation of thyroid cancer cells; while quinones and terpenoids modified Nrf2 signaling in thyroid cell lines. Conclusion: Natural compounds that modify the activity of the Nrf2 pathway should be evaluated carefully, not only for their potential to be used as therapeutic agents for thyroid disorders, but also for their thyroidal safety when used for the prevention and treatment of non-thyroidal diseases.

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Thyroglobulin as a negative marker for malignancy in canine and human breast tumors

Hwang

Yang

Woo

et al. 2021

Molecular Carcinogenesis

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Canine mammary gland tumors (CMTs) are the most common tumor type in female dogs. This study evaluated the expression pattern and role of thyroglobulin (Tg) in CMT and in human breast cancer (HBC). CMT samples were subjected to fine‐needle aspiration, primary cell culture, and histopathology. The expression level of Tg was higher in benign CMT than in malignant CMT (mCMT) primary cells, particularly in the epithelial lineage. Moreover, treatment with Tg enhanced the sensitivity of doxorubicin in mCMT epithelial cells and mitigated proinflammatory response by increasing nuclear factor erythroid 2‐related factor 2 (Nrf2). The proximal region of the Tg promoter was hypermethylated in mCMT epithelial cells, silencing Tg expression with concurrent downregulation of Nrf2‐mediated antioxidant signaling. An identical pattern of Tg expression was observed in cytological and tissue samples. Tissue microarray analysis showed that Tg was highly expressed in normal and benign tissues when compared with their malignant counterparts, which was diminished along with higher histological grades. The survival rate was significantly higher in HBC patients with high Tg expression than those with low Tg expression. This study also showed that the progression of HBC is accompanied by the reduction of Tg expression along with augmentation of proinflammatory signaling. Our data suggested that Tg could be a negative indicator of malignancy in canine and human breast neoplasia

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NFE2-Related Transcription Factor 2 Coordinates Antioxidant Defense with Thyroglobulin Production and Iodination in the Thyroid Gland

Abstract: Nrf2 exerts pleiotropic roles in the thyroid gland to couple cell stress defense mechanisms to iodide metabolism and the thyroid hormone synthesis machinery, both under basal conditions and in response to excess iodide.

Cited by 30 publications

References 82 publications

Class III PI3K Vps34 Controls Thyroid Hormone Production by Regulating Thyroglobulin Iodination, Lysosomal Proteolysis, and Tissue Homeostasis

Class III PI3K Vps34 Controls Thyroid Hormone Production by Regulating Thyroglobulin Iodination, Lysosomal Proteolysis, and Tissue Homeostasis

Impact of Antioxidant Natural Compounds on the Thyroid Gland and Implication of the Keap1/Nrf2 Signaling Pathway

Thyroglobulin as a negative marker for malignancy in canine and human breast tumors

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