RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase

Knauf, Jeffrey A.; Kuroda, Hiroaki; Basu, Saswata; Fagin, James A.

doi:10.1038/sj.onc.1206602

Cited by 160 publications

(111 citation statements)

References 54 publications

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“…However, a threshold of Ras oncogene expression must be present for these effects to become apparent (28). Our data indicated that endogenous levels of Hras G12V were not sufficient to induce hypothyroidism or to negatively impact thyroid hormonogenesis, which may be due to insufficient MAPK activation (29), which our data strongly implicate in this process (38).…”

Section: Discussionmentioning

confidence: 58%

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: Discussionmentioning

confidence: 58%

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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“…A recent study by Knauf et al (2003) demonstrated that acute expression of RET/PTC3, H-Ras, or constitutively activated MEK-1 could all block TSH-induced expression of thyroglobulin and sodium-iodide symporter (NIS) in PCCL3 thyroid cells. This study also demonstrated that treatment of cells with MEK inhibitors could restore the expression of thyroglobulin and NIS.…”

Section: Therapeutic Potential Of Inhibiting the Map Kinase Pathway Umentioning

confidence: 99%

BRAF mutation in thyroid cancer

Xing¹

2005

Endocrine Related Cancer

1,183

976

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Genetic alteration is the driving force for thyroid tumorigenesis and progression, based upon which novel approaches to the management of thyroid cancer can be developed. A recent important genetic finding in thyroid cancer is the oncogenic T1799A transversion mutation of BRAF (the gene for the B-type Raf kinase, BRAF). Since the initial report of this mutation in thyroid cancer 2 years ago, rapid advancements have been made. BRAF mutation is the most common genetic alteration in thyroid cancer, occurring in about 45% of sporadic papillary thyroid cancers (PTCs), particularly in the relatively aggressive subtypes, such as the tall-cell PTC. This mutation is mutually exclusive with other common genetic alterations, supporting its independent oncogenic role, as demonstrated by transgenic mouse studies that showed BRAF mutation-initiated development of PTC and its transition to anaplastic thyroid cancer. BRAF mutation is mutually exclusive with RET/PTC rearrangement, and also displays a reciprocal age association with this common genetic alteration in thyroid cancer. The T1799A BRAF mutation occurs exclusively in PTC and PTC-derived anaplastic thyroid cancer and is a specific diagnostic marker for this cancer when identified in cytological and histological specimens. This mutation is associated with a poorer clinicopathological outcome and is a novel independent molecular prognostic marker in the risk evaluation of thyroid cancer. Moreover, preclinical and clinical evaluations of the therapeutic value of novel specific mitogen-activated protein kinase pathway inhibitors in thyroid cancer are anticipated. This newly discovered BRAF mutation may prove to have an important impact on thyroid cancer in the clinic.Endocrine-Related Cancer (2005) 12 245-262

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“…RET/PTC result from the fusion of the tyrosine kinase domain of the RET receptor with the N-terminus of heterologous proteins (9). RET tyrosine 1062 (Y1062) plays an important role in RET and RET/PTC signaling, acting as the binding site for several proteins, thus leading to ERK and PI3K (phosphoinositide 3-kinase)/AKT signaling (12)(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells

et al. 2012

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CD44 is a marker of cancer stem-like cells and epithelial-mesenchymal transition that is overexpressed in many cancer types, including thyroid carcinoma. At extracellular and intramembranous domains, CD44 undergoes sequential metalloprotease-and g-secretase-mediated proteolytic cleavage, releasing the intracellular protein fragment CD44-ICD, which translocates to the nucleus and activates gene transcription. Here, we show that CD44-ICD binds to the transcription factor CREB, increasing S133 phosphorylation and CREB-mediated gene transcription. CD44-ICD enhanced CREB recruitment to the cyclin D1 promoter, promoting cyclin D1 transcription and cell proliferation. Thyroid carcinoma cells harboring activated RET/PTC, RAS, or BRAF oncogenes exhibited CD44 cleavage and CD44-ICD accumulation. Chemical blockade of RET/PTC, BRAF, metalloprotease, or g-secretase were each sufficient to blunt CD44 processing. Furthermore, thyroid cancer cell proliferation was obstructed by RNA interference-mediated knockdown of CD44 or inhibition of g-secretase and adoptive CD44-ICD overexpression rescued cell proliferation. Together, these findings reveal a CD44-CREB signaling pathway that is needed to sustain cancer cell proliferation, potentially offering new molecular targets for therapeutic intervention in thyroid carcinoma. Cancer Res; 72(6);

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RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase

Cited by 160 publications

References 54 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

BRAF mutation in thyroid cancer

CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells

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