The RET p.G533C Mutation Confers Predisposition to Multiple Endocrine Neoplasia Type 2A in a Brazilian Kindred and Is Able to Induce a Malignant Phenotype in Vitro and in Vivo

The RET p.G533C Mutation Confers Predisposition to Multiple Endocrine Neoplasia Type 2A in a Brazilian Kindred and Is Able to Induce a Malignant Phenotype in Vitro and in Vivo

Author Oliveira, Mariana N. L. Autor UNIFESP Google Scholar
Hemerly, Jefferson P. Autor UNIFESP Google Scholar
Bastos, Andre U. Autor UNIFESP Google Scholar
Tamanaha, Rosana Autor UNIFESP Google Scholar
Latini, Flavia R. M. Autor UNIFESP Google Scholar
Camacho, Cleber P. Autor UNIFESP Google Scholar
Impellizzeri, Anelise Google Scholar
Maciel, Rui M. B. Autor UNIFESP Google Scholar
Cerutti, Janete M. Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Universidade Federal de Minas Gerais (UFMG)
Abstract Background: We have previously described a p.G533C substitution in the rearranged during transfection (RET) oncogene in a large family with medullary thyroid carcinoma. Here, we explore the functional transforming potential of RET p.G533C mutation.Methods: Plasmids expressing RET mutants (p.G533C and p.C634Y) and RET wild type were stable transfected into a rat thyroid cell line (PCCL3). Biological and biochemical effects of RET p.G533C were investigated both in vitro and in vivo. Moreover, we report the first case of pheochromocytoma among the RET p.G533C-carriers in this Brazilian family and explore the RET mutational status in DNA isolated from pheochromocytoma.Results: Ectopic expression of RET p.G533C and p.C634Y activates RET/MAPK/ERK pathway at similar levels and significantly increased cell proliferation, compared with RET wild type. We additionally show that p.G533C increased cell viability, anchorage-independent growth, and micronuclei formation while reducing apoptosis, hallmarks of the malignant phenotype. RET p.G533C down-regulates the expression of thyroid specific genes in PCCL3. Moreover, RET p.G533C-expressing cells were able to induce liver metastasis in nude mice. Finally, we described two novel RET variants (G548V and S556T) in the DNA isolated from pheochromocytoma while they were absent in the DNA isolated from blood.Conclusions: Our in vitro and in vivo analysis indicates that this mutation confers a malignant phenotype to PCCL3 cells. These findings, in association with the report of first case of pheochromocytoma in the Brazilian kindred, suggest that this noncysteine mutation may be more aggressive than was initially considered.
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Grant number FAPESP: 05/60330-8
FAPESP: 06/60402-1
FAPESP: 09/11257-7
Date 2011-09-01
Published in Thyroid. New Rochelle: Mary Ann Liebert Inc, v. 21, n. 9, p. 975-985, 2011.
ISSN 1050-7256 (Sherpa/Romeo, impact factor)
Publisher Mary Ann Liebert Inc
Extent 975-985
Origin http://dx.doi.org/10.1089/thy.2010.0190
Access rights Closed access
Type Article
Web of Science ID WOS:000294768800006
URI http://repositorio.unifesp.br/handle/11600/34022

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