Tissue-specific Carcinogenesis in Transgenic Mice Expressing the RET Proto-Oncogene with a Multiple Endocrine Neoplasia Type 2A Mutation
2000
Germ line mutations of the RET proto-oncogene are
responsible for the development of multiple endocrine neoplasia type 2A
(MEN 2A), an inherited cancer syndrome characterized by medullary
thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. To
study the mechanism of tissue-specific tumor development by
RET with a MEN2A (cysteine
634→arginine) mutation, we generated transgenic mice by introducing
the RET-MEN2A gene fused to Moloney murine leukemia
virus long terminal repeat. Expression of the transgene and its product
was detected at variable levels in a variety of tissues including
thyroid, heart, liver, colon, parotid gland, and brain. All of 29 mice
analyzed developed thyroid C-cell hyperplasia or medullary carcinoma,
accompanying high levels of serum calcitonin. In addition, development
of mammary or parotid gland adenocarcinoma was observed in one-half of
the transgenic mice. RET dimerization and its complex formation with
Shc and Grb2 adaptor proteins were detected in tumor tissues.
Unexpectedly, no tumor formation was found in other tissues despite
RET-MEN2A expression where RET dimerization was
undetectable. Because these tissues but not tumors expressed glial cell
line-derived neurotrophic factor family receptor α (GFRα) at high
levels, this suggested that GFRα expression may interfere in the
dimerization of the RET-MEN2A mutant proteins, leading to
tissue-specific tumor development in vivo .
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