CHARACTERIZATION OF RET ONCOGENIC ACTIVATION IN MEN2 INHERITED CANCERSYNDROMES

Germline mutations of c-ret, encoding a receptor-type tyrosine kinase, were found to be associated with variants of multiple endocrine neopl asia type 2 (MEN2A, MEN2B), and familial medullary thyroid carcinoma. NIH3T3 stable transfectants expressing RET with a mutation of MEN2A (M EN2A/RET) or MEN2B (MEN2B/RET) gained a transformed morphology, formed colonies in soft agar, and formed tumors in nude mice. These results confirmed that both MEN2A/RET and MEN2B/RET exert dominant transformin g activities in NIH/3T3 cells. However, in contrast to their clinical manifestation, transfectents expressing MEN2A/RET exhibited a higher t umorigenicity in nude mice than transfectants expressing MEN2B/RET, su ggesting that full activation of MEN2B/RET may depend on the presence of its ligand and/or substrates that are absent in NIH/3T3 cells. No c hange in the cellular localization of the mutated RET proteins was obs erved compared to c-RET. Interestingly, ret activation in NIH/3T3 cell s appeared to be associated with up-regulation of homologous gap-junct ional intercellular communication and increased expression of a gap-ju nctional protein, connexin43.