Evaluation of potential mechanisms underlying genotype-phenotype correlations in multiple endocrine neoplasia type 2
| Autor: | Matthias Drosten, Brigitte M. Pützer, Tomáš Racek, Andrea Tannapfel, Nikica Mise |
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| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
medicine.medical_specialty Genotype Statistics as Topic Multiple endocrine neoplasia type 2 Apoptosis Multiple Endocrine Neoplasia Type 2a Multiple Endocrine Neoplasia Type 2b Biology medicine.disease_cause Transfection Mice Internal medicine Genetics medicine Animals Thyroid Neoplasms Multiple endocrine neoplasia Molecular Biology Cell Line Transformed Cell Proliferation Mutation Proto-Oncogene Proteins c-ret medicine.disease Phenotype Endocrinology Cell Transformation Neoplastic Carcinoma Medullary NIH 3T3 Cells Mutant Proteins Carcinogenesis Multiple endocrine neoplasia type 2b Signal Transduction |
| Zdroj: | Oncogene. 25(50) |
| ISSN: | 0950-9232 |
| Popis: | Distinct dominant activating mutations in the RET proto-oncogene are responsible for the development of multiple endocrine neoplasia type 2 (MEN 2). Concise examination of the mutated codons led to the detection of a striking genotype-phenotype correlation between the mutated codon and the MEN 2 phenotype in terms of onset and aggressiveness of the disease, suggesting that manifestation and clinical progression is conditioned by the type of mutation. To gain insight into the molecular basis for this genotype-phenotype correlation, we analysed the impact of common and rare mutations identified in MEN 2A (C609Y, C634R), MEN 2B (A883F, M918T) and familial medullary thyroid carcinoma (Y791F) patients on several aspects of cell transformation, including proliferation, apoptosis, anchorage-independent growth and signaling. We found that tumor cells arising from distinct extracellular or intracellular MEN 2 mutations clearly differ in their proliferation properties owing to the activation of different molecular pathways, but importantly, also in resistance to apoptosis. Whereas MEN 2A mutants resulted in accelerated cell proliferation, MEN 2B-RET mutants significantly enhanced suppression of apoptosis, which may account, at least partially, for some of the clinical differences in MEN 2 patients. |
| Databáze: | OpenAIRE |
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