Evaluation of potential mechanisms underlying genotype–phenotype correlations in multiple endocrine neoplasia type 2

Miše, Nikica; Drosten, Matthias; Raček, Tomáš; Tannapfel, Andrea; Pützer, Brigitte M.

doi:10.1038/sj.onc.1209669

Cited by 41 publications

(47 citation statements)

References 45 publications

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“…In order to provide structural insights into the best functionally characterized RET kinase domain mutations found in MEN2 (Iwashita et al 1996(Iwashita et al , 1999) and taken as a template the crystal structure of RET catalytic domain bound to Vandetanib (PDB: 2IVU), we rationalized about the mechanisms behind the more common (and bestcharacterized) disease phenotype-specific mutations found in MEN2: E768D, L790F, Y791F, S891A, V804M/L (FMTC) and A883F, M918T (MEN2B) (Iwashita et al 1999, Plaza Menacho et al 2005, Mise et al 2006, Fig. 3A.…”

Section: Mapping and Functional Prediction Of Men2 Mutations Targetinmentioning

confidence: 99%

Structure and function of RET in multiple endocrine neoplasia type 2

Plaza-Menacho¹

2018

Endocrine-Related Cancer

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Correspondence should be addressed to I Plaza-Menacho: iplaza@cnio.esThis paper is part of a thematic review section on 25 Years of RET and MEN2. The guest editors for this section were Lois Mulligan and Frank Weber. AbstractIt has been twenty-five years since the discovery of oncogenic germline RET mutations as the cause of multiple endocrine neoplasia type 2 (MEN2). Intensive work over the last two and a half decades on RET genetics, signaling and cell biology has provided the current bases for the genotype-phenotype and functional correlations within this cancer syndrome. On the contrary, the structural and molecular basis for RET tyrosine kinase domain activation and oncogenic deregulation has remained largely elusive. Recent studies with a strong crystallographic and biochemical focus have started to elucidate key insights into such molecular and atomic details revealing unexpected and private mechanisms of actions and molecular determinants not previously envisioned. This review focuses on the structure and function of the RET receptor, and in particular, on what a more detailed view of the protein itself and what the current structural and molecular information tell us about the genotype and phenotype relationships in the cancer syndrome MEN2.

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Section: Mapping and Functional Prediction Of Men2 Mutations Targetinmentioning

confidence: 99%

Structure and function of RET in multiple endocrine neoplasia type 2

Plaza-Menacho¹

2018

Endocrine-Related Cancer

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“…As oncogenic RET stimulates proliferation and blocks apoptosis, 8 and disruption of oncogenic RET activity by intratumoral transduction of primary MTC in transgenic mice with wild-type Ad.RETDTK decreased cell viability, 20 we studied whether systemic treatment with truncated RET from the targeted vector impairs pathologically altered tumors to the point that apoptosis sets in. For this purpose, we performed TdT-mediated dUTP-biotin nick end labeling assays on paraffin-embedded residual tumor tissues from tail-vein injected mice.…”

Section: Systemic Targeting Of Mtc By Peptide-tagged Admentioning

confidence: 99%

“…5 This causes ligand-independent homodimerization and constitutive autophosphorylation, and activation of the RET kinase, leading to the stimulation of a complex network of signal transduction pathways that contribute to dysregulated growth and survival. 7,8 Activated oncogenes such as RET are highly attractive targets for the development of anticancer agents. 9 Principles of RET inhibition in MTC cells include molecular strategies to interfere with its kinase activity by small molecules [10][11][12] and receptor dimerization using aptamers or soluble RET ectodomain.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of systemic targeting of RET oncogene-based MTC with tumor-selective peptide-tagged Ad vectors in clinical mouse models

et al. 2011

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Significant advantage of targeted antitumoral treatment consists in the possibility to restrict maximum therapeutic efficacy to the malignant cell population by reducing toxicity in healthy tissues. Using different clinical models for aggressive medullary thyroid carcinoma (MTC), we have recently identified peptide ligands that bind highly selective to tumor cells. By linking the most convincing SRESPHP peptide to an adenoviral (Ad) vector expressing the MTC-related oncogene inhibitor RETDTK, gene transfer was specifically directed to neoplastic tissue after systemic virus administration. We show that peptide-mediated delivery of RETDTK significantly enhanced apoptosis, resulting in a strong inhibition of orthotopic and xenograft tumor growth. Conversely, tumors treated with controls expanded their initial size without notable cell death. According to the therapeutic effect, strong virus accumulation was found exclusively in thyroid carcinomas. Strikingly, application of native tropism depleted viral vector linked to tumor-selective peptide was accompanied by a substantial reduction of Ad binding to the liver. Of note, single systemic injection of a low dose (10e8 pfu/mouse) of MTC-specific Ad.RETDTK induced regression of multiple tumors at different sites in all treated animals. In sum, our results open up the possibility for an efficient cancer cell-specific therapy of primary MTC, their migrating populations and potentially metastases.

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“…The RET protooncogene has 21 exons and encodes a tyrosine-kinase receptor expressed in thyroid parafollicular C-cells. Hyperactivation of the receptor leads to the induction of downstream signals responsible for oncogenesis (Mise et al 2006). While it has long been held that the parafollicular C-cells are of neural crest origin, a recent lineage tracing study suggested that anterior endoderm, and not the neural crest, is the only source of differentiated C-cells in mice (Johansson et al 2015).…”

Section: Genetics Of Men2bmentioning

confidence: 99%

A comprehensive review on MEN2B

Castinetti¹,

Moley²,

Mulligan³

et al. 2018

Endocrine-Related Cancer

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MEN2B is a very rare autosomal dominant hereditary tumor syndrome associated with medullary thyroid carcinoma (MTC) in 100% cases, pheochromocytoma in 50% cases and multiple extra-endocrine features, many of which can be quite disabling. Only few data are available in the literature. The aim of this review is to try to give further insights into the natural history of the disease and to point out the missing evidence that would help clinicians optimize the management of such patients. MEN2B is mainly characterized by the early occurrence of MTC, which led the American Thyroid Association to recommend preventive thyroidectomy before the age of 1 year. However, as the majority of mutations are de novo, improved knowledge of the nonendocrine signs would help to lower the age of diagnosis and improve long-term outcomes. Future large-scale studies will be aimed at characterizing more in detail the main characteristics and outcomes of MEN2B.

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Evaluation of potential mechanisms underlying genotype–phenotype correlations in multiple endocrine neoplasia type 2

Cited by 41 publications

References 45 publications

Structure and function of RET in multiple endocrine neoplasia type 2

Structure and function of RET in multiple endocrine neoplasia type 2

Evaluation of systemic targeting of RET oncogene-based MTC with tumor-selective peptide-tagged Ad vectors in clinical mouse models

A comprehensive review on MEN2B

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