Characterization of ret oncogenic activation in MEN2 inherited cancer syndromes.
Germline mutations of c-ret, encoding a receptor-type tyrosine kinase, were found to be associated with variants of multiple endocrine neoplasia type 2 (MEN2A, MEN2B), and familial medullary thyroid carcinoma. NIH/3T3 stable transfectants expressing RET with a mutation of MEN2A (MEN2A/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 transforming activities in NIH/3T3 cells. However, in contrast to their clinical manifestation, transfectants expressing MEN2A/RET exhibited a higher tumorigenicity in nude mice than transfectants expressing MEN2B/RET may depend on the presence of its ligand and/or substrates that are absent in NIH/3T3 cells. No change in the cellular localization of the mutated RET proteins was observed compared to c-RET. Interestingly, ret activation in NIT/3T3 cells appeared to be associated with up-regulation of homologous gap-junctional intercellular communication and increased expression of a gap-junctional protein, connexin43.
Xing
S
S
Department of Physiology and Internal Medicine, Ohio State University, Columbus 43210, USA.
Smanik
P A
PA
Oglesbee
M J
MJ
Trosko
J E
JE
Mazzaferri
E L
EL
Jhiang
S M
SM
D016475:3T3 Cells; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D018031:Connexin 43 / Q000235:genetics; D003593:Cytoplasm / Q000737:chemistry; D029721:Drosophila Proteins; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D018814:Multiple Endocrine Neoplasia Type 2b / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D014162:Transfection
D018031:Connexin 43; D029721:Drosophila Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse