Hyperthyroidism and Papillary Thyroid Carcinoma in Thyrotropin Receptor D633H Mutant Mice

Jaeschke, Holger; Undeutsch, Henriette; Patyra, Konrad; Löf, Christoffer; Eszlinger, Markus; Khalil, Moosa; Jannari, Meeri; Makkonen, Kristiina; Toppari, Jorma; Zhang, Fuping; Poutanen, Matti; Paschke, Ralf; Kero, Jukka

doi:10.1089/thy.2018.0041

Cited by 17 publications

(36 citation statements)

References 65 publications

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“…Measurements of sera of mice treated with LT3, LT4, and PTU showed expected values; increased fT3, increased fT4, and decreased fT4 and increased TSH, respectively (Figure S2). Furthermore, serum fT3 and fT4 levels of our Empty mice were approximately consistent with those of C57BL/6 mice measured in other studies 25,26 27 .…”

Section: Resultssupporting

confidence: 89%

Thyroid hormone economy in mice overexpressing iodothyronine deiodinases

et al. 2022

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In peripheral tissues, triiodothyronine (T3) production and consequent thyroid hormone actions are mainly regulated by iodothyronine deiodinases (DIOs) classified into 3 types: D1, D2, and D3. We aimed to investigate the effects of peripheral DIOs on thyroid hormone economy independent of the hypothalamus‐pituitary‐thyroid axis. We cloned coding sequences of human DIOs with FLAG‐tag and HiBiT‐tag sequences into a pcDNA3.1 vector. To obtain full‐length proteins, we modified these vectors by cloning the selenocysteine insertion sequence of each DIO (SECIS vectors). Western blot analyses and HiBiT lytic assay using HEK293T cells revealed that SECIS vectors expressed full‐length proteins with substantial activity. Subsequently, in vivo transfections of pLIVE‐based SECIS vectors into male C57BL/6J mice were performed by hydrodynamic gene delivery to generate mice overexpressing DIOs predominantly in the liver (D1, D2, and D3 mice). After 7 days from transfections, mice were analyzed to clarify phenotypes. To summarize, serum thyroid hormone levels did not change in D1 mice but D2 mice had higher serum free T3 levels. D3 mice developed hypothyroidism with higher serum reverse T3 (rT3) levels. Transfections with levothyroxine administration suggested that thyroid hormone action was upregulated in D2 mice. Our DIO‐overexpressing mice provided insights on the physiological properties of upregulated DIOs: D2 augments local thyroid hormone action and recruits T3 into the circulation: D3 decreases circulating T3 and T4 levels with elevated rT3, leading to consumptive hypothyroidism. As D3 mice are expected to be a novel hypothyroidism model, they can contribute to progress in the field of thyroid hormone economy and action.

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Section: Resultssupporting

confidence: 89%

Thyroid hormone economy in mice overexpressing iodothyronine deiodinases

et al. 2022

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“…An investigation of how noncanonical Gα 12/13 signaling is preferentially activated in thyroid cancer cells would be intriguing. Gain- or loss-of-function mutations in TSHR have been reported to be associated with the abnormal activation of downstream signaling ( 30 , 31 ). For example, in transfected COS-7 cells, L653A TSHR expression was shown to reduce the downstream production of different G proteins to a different extent, as stimulated cAMP was decreased by 62%, while stimulated IP production was decreased 12% compared to that in cells expressing WT TSHR ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Crosstalk Between Abnormal TSHR Signaling Activation and PTEN/PI3K in the Dedifferentiation of Thyroid Cancer Cells

Fěng

Han

et al. 2021

Front. Oncol.

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Iodide uptake and the metabolism of thyroid cells are regulated by thyrotropin (TSH)-TSH receptor (TSHR) signaling. Thus, it is necessary to elevate serum TSH levels by T4 withdraw or rTSH administration to facilitate radioiodide (131I) therapy for differentiated thyroid cancer (DTC). However, non-iodide-avid metastases of DTC which is dedifferentiated do not respond to stimulation by high levels of TSH, suggesting abnormal TSH-TSHR signal transduction in cancer cells. In addition, PI3K/AKT/mTOR signaling activation has been shown to be associated with the dedifferentiated phenotype of thyroid cancer, but the mechanism remains elusive. Therefore, in this study, we aimed to explore the role of abnormal TSH-TSHR signaling activation in regulating iodide uptake and cell mobility in thyroid cancer and its relationship with PI3K/AKT/mTOR signaling. We found that in thyroid cancer cells, TSH binds TSHR coupled to the Gα12/13 protein and then activates RhoA through interacting with leukemia associated RhoA guanine exchange factor (LARG). This results in a promigration tumorigenic phenotype independent of canonical TSHR-GαS signaling that regulates the expression of molecules involved in iodine uptake and metabolism. We observed that signaling pathways downstream of Gα12/13 signaling were increased, while that of Gαs signaling was decreased in thyroid cancer cells undergoing dedifferentiation compared to control cells following stimulation with different levels of TSH. PI3K/AKT/mTOR signaling activation enhanced Gα12/13 signaling through increasing LARG levels but also inhibited the expression of molecules downstream of Gαs signaling, including thyroid-specific molecules, and iodide uptake. In summary, our results demonstrate the noncanonical activation of TSH-TSHR signaling and its role in increasing the cell mobility and dedifferentiation of thyroid cancer through crosstalk with PI3K/AKT/mTOR signaling.

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“…This novel finding notwithstanding, not all toxic adenomas display an EZH1 mutation and from screening of other benign and malignant thyroid tumours it appears that EZH1 mutations at least in codon 571 are not principally involved in regulation of proliferation in these tumours [30]. In the future further mechanistic insights into the development of macroscopic thyroid autonomy may be derived from the first gain-of-function TSHR mutant mouse model that has only very recently been established [31].…”

Section: Understanding the Biological Consequences Of Tshr Mutations mentioning

confidence: 99%

Constitutive TSH receptor activation as a hallmark of thyroid autonomy

Führer

2020

Endocrine

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Since its cloning more than 30 years ago, the thyrotropin receptor (TSHR) has emerged as a pivotal player in thyroid physiology and pathophysiology. In particular, hyperthyroidism due to autoimmune disease or thyroid autonomy is linked with TSHR activation via autoantibodies or mutations respectively. This review summarises clinical aspects of constitutive TSH receptor activation by naturally occurring somatic or germline TSHR mutations resulting in TSH-independent thyroid function and cell proliferation.

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Hyperthyroidism and Papillary Thyroid Carcinoma in Thyrotropin Receptor D633H Mutant Mice

Abstract: This is the first study to reveal the dynamic age-, sex-, and genotype-dependent development of NAH. Furthermore, the study shows that a constitutively active TSHR can trigger a malignant transformation of thyrocytes.

Cited by 17 publications

References 65 publications

Thyroid hormone economy in mice overexpressing iodothyronine deiodinases

Thyroid hormone economy in mice overexpressing iodothyronine deiodinases

Crosstalk Between Abnormal TSHR Signaling Activation and PTEN/PI3K in the Dedifferentiation of Thyroid Cancer Cells

Constitutive TSH receptor activation as a hallmark of thyroid autonomy

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