Thyrocyte-specific Gq/G11 deficiency impairs thyroid function and prevents goiter development

Kero, Jukka; Ahmed, Kashan; Wettschureck, Nina; Tunaru, Sorin; Wintermantel, Tim; Greiner, Erich F.; Schütz, Günther; Offermanns, Stefan

doi:10.1172/jci30380

Cited by 118 publications

(101 citation statements)

References 58 publications

(50 reference statements)

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“…The potential significance of TSH action in the initial events associated with Braf-induced thyroid cell transformation is further supported by the attenuated phenotype seen in mice with thyroid-specific deletion of Gsα. However, the fact that Gsα deletion did not prevent development of PTCs is consistent with the evidence that other TSH-activated downstream pathways, such as Gq/G11, also play a critical role in thyroid cell growth (44).…”

Section: Discussionsupporting

confidence: 83%

Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice

Franco¹,

Malaguarnera²,

Refetoff

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

199

198

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Mutations of BRAF are found in ∼45% of papillary thyroid cancers and are enriched in tumors with more aggressive properties. We developed mice with a thyroid-specific knock-in of oncogenic Braf (LSL-Braf V600E /TPO-Cre) to explore the role of endogenous expression of this oncoprotein on tumor initiation and progression. In contrast to other Braf-induced mouse models of tumorigenesis (i.e., melanomas and lung), in which knock-in of Braf V600E induces mostly benign lesions, Braf-expressing thyrocytes become transformed and progress to invasive carcinomas with a very short latency, a process that is dampened by treatment with an allosteric MEK inhibitor. These mice also become profoundly hypothyroid due to deregulation of genes involved in thyroid hormone biosynthesis and consequently have high TSH levels. To determine whether TSH signaling cooperates with oncogenic Braf in this process, we first crossed LSL-Braf V600E /TPO-Cre with TshR knockout mice. Although oncogenic Braf was appropriately activated in thyroid follicular cells of these mice, they had a lower mitotic index and were not transformed. Thyroid-specific deletion of the Gsα gene in LSL-Braf V600E /TPO-Cre/Gnas-E1 fl/fl mice also resulted in an attenuated cancer phenotype, indicating that the cooperation of TshR with oncogenic Braf is mediated in part by cAMP signaling. Once tumors were established in mice with wild-type TshR, suppression of TSH did not revert the phenotype. These data demonstrate the key role of TSH signaling in Braf-induced papillary thyroid cancer initiation and provide experimental support for recent observations in humans pointing to a strong association between TSH levels and thyroid cancer incidence.T hyroid follicular cells are among a select group of cell types, which includes other endocrine cell lineages, melanocytes, and Schwann cells, in which the second messenger cAMP helps promote DNA synthesis and cell proliferation. In thyroid cells this pathway is engaged via constitutive and ligand-induced activation of the TSH receptor (TSHR), which, however, requires concomitant activation of receptor tyrosine kinase signaling for growth to ensue (1-3). It is therefore fitting that distinct subtypes of thyroid neoplasms are associated with oncogenes encoding effectors of the TSH-TSH receptor-adenylyl cyclase pathway (i.e., TSHR and GNAS) (4, 5) or with proteins that signal along canonical receptor tyrosine kinase pathways. Thus, rearrangements of genes encoding the receptor tyrosine kinases RET or NTRK, as well as point mutations of all three RAS genes and of the serine kinase BRAF, are found in a mutually exclusive manner in papillary thyroid cancers (PTC), the most prevalent form of the disease (6-8). The activating point mutation BRAF T1799A , which encodes for BRAF V600E , is the most common genetic abnormality in papillary thyroid cancer and constitutively activates the MEK-ERK pathway. Thyroid cancers with BRAF mutations have distinctive pathological and phenotypic features: i.e., they are more frequently invasive, have highe...

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Section: Discussionsupporting

confidence: 83%

Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice

Franco¹,

Malaguarnera²,

Refetoff

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

199

198

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“…In an in vitro study, the C636W mutant stimulated the Gs-adenylyl cyclase pathway in a constitutive manner; however, activation of Gq-phospholipase C stimulated by TSH was markedly reduced compared with the WT. Based on these findings, the authors suggested that the lack of goiter in their patient might be due to impairment of the Gq-phospholipase C signal pathway because Gq-phospholipase C is involved in thyroid hormone synthesis and growth of the thyroid gland as well as the Gs-adenylyl cyclase pathway (3). In this context, we compared the activation capacity of Gq-phospholipase C between M453R and M453T; however, both mutants had completely lost the capacity to activate this pathway.…”

Section: Discussionmentioning

confidence: 98%

“…This receptor consists of seven transmembrane domains (TMDs) and a large extracellular domain (ECD) that mediates the effect of TSH in thyroid development, growth, and hormone synthesis (1,2). TSH binds the TSHR and activates two signal transduction pathways: the Gs/adenylyl cyclase and Gq-phospholipase C pathways (2,3). The Gs/adenylyl cyclase system is thought to be important for most TSH-induced effects on the growth and the function of the thyroid gland (1,2).…”

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confidence: 99%

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A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation

et al. 2014

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Background: Hyperthyroidism caused by activating mutations of the thyrotropin receptor gene (TSHR) is rare in the pediatric population. Methods: We found a Japanese family with hyperthyroidism without autoantibody. DNA sequence analysis of TSHR was undertaken in this family. The functional consequences for the Gs-adenylyl cyclase and Gq/11-phospholipase C signaling pathways and cell surface expression of receptors were determined in vitro using transiently transfected human embryonic kidney 293 cells. results: We identified a heterozygous mutation (M453R) in exon 10 of TSHR. In this family, this mutation was found in all individuals who exhibited hyperthyroidism. The results showed that this mutation resulted in constitutive activation of the Gs-adenylyl cyclase system. However, this mutation also caused a reduction in the activation capacity of the Gq/11-phospholipase C pathway, compared with the wild type. conclusion: We demonstrate that the M453R mutation is the cause of nonautoimmune hyperthyroidism.

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“…A known TSH-dependent but cAMP-independent signaling pathway arises from coupling of the TSHR to G q/11 proteins, activation of phospholipase C, and formation of inositol phosphates (5,18,19). Phospholipase Cdependent pathways have recently been shown to be required for iodine organification and thyroid hormone secretion and for the adaptive growth of the thyroid gland (20). Finally, G 12/13 coupling of the TSHR has been shown in primary human thyrocytes and was suggested to be related to growth or differen-* This work was supported by the Deutsche Forschungsgemeinschaft Grant TR17, project C4.…”

mentioning

confidence: 99%

G13-dependent Activation of MAPK by Thyrotropin

Büch

Biebermann

Kalwa

et al. 2008

Journal of Biological Chemistry

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Thyrocyte-specific Gq/G11 deficiency impairs thyroid function and prevents goiter development

Cited by 118 publications

References 58 publications

Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice

Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice

A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation

G13-dependent Activation of MAPK by Thyrotropin

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