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Activation of RET as a Dominant Transforming Gene by Germline Mutations of MEN2A and MEN2B

1995; American Association for the Advancement of Science; Volume: 267; Issue: 5196 Linguagem: Inglês

10.1126/science.7824936

1095-9203

Massimo Santoro, Francesca Carlomagno, Alfredo Romano, Donald P. Bottaro, Nina Dathan, Michèle Grieco, Alfredo Fusco, Giancarlo Vecchio, Brona Matoskova, Matthias H. Kraus, Pier Paolo Di Fiore,

Epigenetics and DNA Methylation

Multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) and familial medullary thyroid carcinoma are dominantly inherited cancer syndromes. All three syndromes are associated with mutations in RET , which encodes a receptor-like tyrosine kinase. The altered RET alleles were shown to be transforming genes in NIH 3T3 cells as a consequence of constitutive activation of the RET kinase. The MEN2A mutation resulted in RET dimerization at steady state, whereas the MEN2B mutation altered RET catalytic properties both quantitatively and qualitatively. Oncogenic conversion of RET in these neoplastic syndromes establishes germline transmission of dominant transforming genes in human cancer.