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Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine
K Kawai1, T Iwashita, H Murakami
1Department of Pathology, Nagoya University School of Medicine, Japan.
Abstract:
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 alpha (GFR alpha) at high levels, this suggested that GFR alpha expression may interfere in the dimerization of the RET-MEN2A mutant proteins, leading to tissue-specific tumor development in vivo.
Insights
Germ line mutations in the RET proto-oncogene cause multiple endocrine neoplasia type 2A (MEN 2A). This study reveals that glial cell line-derived neurotrophic factor family receptor alpha (GFRα) expression interferes with RET dimerization, leading to tissue-specific tumor development.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Germ line mutations in the RET proto-oncogene are the primary cause of multiple endocrine neoplasia type 2A (MEN 2A), a hereditary cancer syndrome.
- MEN 2A is characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia.
Purpose of the Study:
- To investigate the mechanism underlying tissue-specific tumor development driven by a RET proto-oncogene with a MEN 2A-associated mutation (cysteine 634 to arginine).
Main Methods:
- Generated transgenic mice carrying the RET-MEN2A gene fused to the Moloney murine leukemia virus long terminal repeat.
- Analyzed transgene expression, RET dimerization, and complex formation with Shc and Grb2 adaptor proteins in various tissues and tumors.
- Assessed the expression levels of glial cell line-derived neurotrophic factor family receptor alpha (GFRα) in different tissues.
Main Results:
- All transgenic mice developed thyroid C-cell hyperplasia or medullary carcinoma, with high serum calcitonin levels.
- Mammary or parotid gland adenocarcinoma developed in approximately half of the transgenic mice.
- RET dimerization was detected in tumor tissues but not in other expressing tissues, which showed high GFRα levels.
Conclusions:
- High GFRα expression in certain tissues may inhibit RET-MEN2A mutant protein dimerization, thereby preventing tumor formation in those specific tissues.
- This suggests that GFRα plays a crucial role in the tissue-specific oncogenic activity of RET in MEN 2A.