Regulation of Type 3 Iodothyronine Deiodinase Expression in Cultured Rat Astrocytes: Role of the Erk Cascade<sup>1</sup>

Pallud, Sophie; Ramaugé, Martine; Gavaret, Jean‐Michel; Lennon, Ana Maria; Munsch, Nicole; Germain, Donald L. St.; Martineau, Pierre; Courtin, Françoise

doi:10.1210/endo.140.6.6834

Cited by 43 publications

(4 citation statements)

References 39 publications

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“…Here we have demonstrated that DIO3 expression is induced in human PTC. D3 induction occurs at transcriptional level and it is likely to be driven by the constitutive activation of the MAPK pathway, which has been previously implicated in D3 upregulation in other pathological conditions (22,(27)(28)(29). Consistently with this hypothesis, we show that samples carrying the BRAF V600E mutation display the highest levels of DIO3 mRNA and activity (Fig.…”

Section: Discussionsupporting

confidence: 88%

Increased Type 3 Deiodinase Expression in Papillary Thyroid Carcinoma

Maia¹,

Romitti²,

Wajner³

et al. 2012

Thyroid

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Background: Thyroid hormone regulates a wide range of cellular activities, including the balance between cell proliferation and differentiation. The thyroid-hormone-inactivating type 3 deiodinase (DIO3, D3) has been shown to be reactivated in human neoplasias. Here, we evaluated DIO3 expression in human papillary thyroid carcinoma (PTC). Methods: Tumor and surrounding normal thyroid tissue were collected from 26 unselected patients with PTC. Clinical data were retrospectively reviewed in medical records. DIO3 mRNA levels were measured by real-time polymerase chain reaction and D3 activity by paper-descendent chromatography. Studies of DIO3 gene regulation were performed in a human PTC-derived cell line (K1 cells). BRAF V600E mutation was identified in DNA from paraffin-embedded tissues by direct sequencing. Immunohistochemistry analyses were performed using a specific human D3 antibody. Results: Increased D3 activity was detected in all 26 PTC samples analyzed as compared with adjacent thyroid tissue. The augmentations in D3 activity were paralleled by increased DIO3 mRNA levels (approximately fivefold). In PTCderived cells, DIO3 transcripts were further upregulated by the transforming growth factor b1 (TGFb1). Interestingly, preincubation with mitogen-activated protein kinase (MAPK) cascade inhibitors U0126 (ERK pathway) and SB203580 (p38 pathway) decreased DIO3 mRNA levels and blocked the TGFb1-induced increase in DIO3 transcripts, suggesting that D3 induction might be mediated through the MAPK signaling pathway. Accordingly, DIO3 mRNA and activity levels were significantly higher in BRAF V600E -mutated samples ( p = 0.001). Increased D3 activity was correlated with tumor size (r = 0.68, p = 0.003), and associated with lymph node ( p = 0.03) or distant metastasis ( p = 0.006) at diagnosis. Conversely, decreased levels of the thyroid-hormone-activating type 2 deiodinase (DIO2) gene were observed in PTC, which might contribute to further decreases in intracellular thyroid hormone levels. Increased D3 expression was also observed in follicular thyroid carcinoma but not in medullary or anaplastic thyroid carcinoma samples. Conclusions: These results indicate that the malignant transformation of thyroid follicular cell toward PTC promotes opposite changes in DIO3 and DIO2 expression by pretranscriptional mechanisms. The association between increased levels of D3 activity and advanced disease further supports a role for intracellular triiodothyronine concentration on the thyroid tumor cell proliferation or/and dedifferentiation.

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Section: Discussionsupporting

confidence: 88%

Increased Type 3 Deiodinase Expression in Papillary Thyroid Carcinoma

Maia¹,

Romitti²,

Wajner³

et al. 2012

Thyroid

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“…Interestingly, siRNA-mediated DIO3 gene silencing decreases cyclin D1 levels while increasing the proportion of cells in the G1 phase of the cell cycle, reducing the proliferation of malignant thyroid cells. A potential role of D3 in tumorigenesis has been postulated due to DIO3 upregulation in several benign and malignant tumors (Pallud et al 1999, Huang et al 2005, Dentice et al . 2007, Romitti et al 2012.…”

Section: Discussionmentioning

confidence: 99%

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

Romitti¹,

Wajner²,

Ceolin³

et al. 2016

Endocrine-Related Cancer

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Type 3 deiodinase (DIO3, D3) is reactivated in human neoplasias. Increased D3 levels in papillary thyroid carcinoma (PTC) have been associated with tumor size and metast atic disease. The objective of this study is to investigate the signaling pathways involved in DIO3 upregulation in PTC. Experiments were performed in human PTC cell lines (K1 and TPC-1 cells) or tumor samples. DIO3 mRNA and activity were evaluated by real-time PCR and ion-exchange column chromatography respectively. Western blot analysis was used to determine the levels of D3 protein. DIO3 gene silencing was performed via siRNA transfection. DIO3 mRNA levels and activity were readily detected in K1 (BRAF V600E ) and, at lower levels, in TPC-1 (RET/PTC1) cells (P!0.007 and PZ0.02 respectively). Similarly, DIO3 mRNA levels were higher in PTC samples harboring the BRAF V600E mutation as compared with those with RET/PTC1 rearrangement or negative for these mutations (P!0.001). Specific inhibition of BRAF oncogene (PLX4032, 3 mM), MEK (U0126, 10-20 mM) or p38 (SB203580, 10-20 mM) signaling was associated with decreases in DIO3 expression in K1 and TPC-1 cells. Additionally, the blockage of the sonic hedgehog (SHH) pathway by cyclopamine (10 mM) resulted in markedly decreases in DIO3 mRNA levels. Interestingly, siRNA-mediated DIO3 silencing induced decreases on cyclin D1 expression and partial G1 phase cell cycle arrest, thereby downregulating cell proliferation. In conclusion, sustained activation of the MAPK and SHH pathways modulate the levels of DIO3 expression in PTC. Importantly, DIO3 silencing was associated with decreases in cell proliferation, thus suggesting a D3 role in tumor growth and aggressiveness.

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“…Not much is known about the mechanism involved in muscle D3 regulation during inflammation. Although D3 can be stimulated via the ERK1/2 and p38 signalling pathways in human non-muscular cells, little is known about these effects in SM (Pallud et al 1999, Wajner et al 2011.…”

Section: Influence Of Illness On Skeletal Muscle Thyroid Hormone Signmentioning

confidence: 99%

Role of thyroid hormone in skeletal muscle physiology

Bloise

Cordeiro

Ortiga-Carvalho

2018

Journal of Endocrinology

140

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Thyroid hormones (TH) are crucial for development, growth, differentiation, metabolism and thermogenesis. Skeletal muscle (SM) contractile function, myogenesis and bioenergetic metabolism are influenced by TH. These effects depend on the presence of the TH transporters MCT8 and MCT10 in the plasma membrane, the expression of TH receptors (THRA or THRB) and hormone availability, which is determined either by the activation of thyroxine (T 4 ) into triiodothyronine (T 3 ) by type 2 iodothyronine deiodinases (D2) or by the inactivation of T 4 into reverse T 3 by deiodinases type 3 (D3). SM relaxation and contraction rates depend on T 3 regulation of myosin expression and energy supplied by substrate oxidation in the mitochondria. The balance between D2 and D3 expression determines TH intracellular levels and thus influences the proliferation and differentiation of satellite cells, indicating an important role of TH in muscle repair and myogenesis. During critical illness, changes in TH levels and in THR and deiodinase expression negatively affect SM function and repair. This review will discuss the influence of TH action on SM contraction, bioenergetics metabolism, myogenesis and repair in health and illness conditions.

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Regulation of Type 3 Iodothyronine Deiodinase Expression in Cultured Rat Astrocytes: Role of the Erk Cascade¹

Cited by 43 publications

References 39 publications

Increased Type 3 Deiodinase Expression in Papillary Thyroid Carcinoma

Increased Type 3 Deiodinase Expression in Papillary Thyroid Carcinoma

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

Role of thyroid hormone in skeletal muscle physiology

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Regulation of Type 3 Iodothyronine Deiodinase Expression in Cultured Rat Astrocytes: Role of the Erk Cascade1

Cited by 43 publications

References 39 publications

Increased Type 3 Deiodinase Expression in Papillary Thyroid Carcinoma

Increased Type 3 Deiodinase Expression in Papillary Thyroid Carcinoma

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

Role of thyroid hormone in skeletal muscle physiology

Contact Info

Product

Resources

About

Regulation of Type 3 Iodothyronine Deiodinase Expression in Cultured Rat Astrocytes: Role of the Erk Cascade¹