A Potential Pathogenetic Mechanism for Multiple Endocrine Neoplasia Type 2 Syndromes Involves ret-Induced Impairment of Terminal Differentiation of Neuroepithelial Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 1996-07, Vol.93 (15), p.7933-7937
• Main Authors: Califano, D., D'Alessio, A., Colucci-D'Amato, G. L., De Vita, G., Monaco, C., Santelli, G., Di Fiore, P. P., Vecchio, G., Fusco, A., Santoro, M., De Franciscis, V.
• Format: Article
• Language: English
• Subjects: Adrenal Gland Neoplasms; Alleles; Animals; Cell Differentiation; Cell growth; Cell lines; Chloramphenicol O-Acetyltransferase - biosynthesis; DNA-Binding Proteins - biosynthesis; Drosophila Proteins; Early Growth Response Protein 1; Genetics; Humans; Immediate-Early Proteins; Medical research; Multiple endocrine neoplasia type 2a; Multiple Endocrine Neoplasia Type 2a - genetics; Multiple Endocrine Neoplasia Type 2a - pathology; Multiple endocrine neoplasia type 2b; Multiple Endocrine Neoplasia Type 2b - genetics; Multiple Endocrine Neoplasia Type 2b - pathology; Mutation; Neurons - cytology; Oncogenes; PC12 Cells; Phenotypes; Pheochromocytoma; Plasmids; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-ret; Proto-Oncogenes; Rats; Receptor Protein-Tyrosine Kinases - biosynthesis; Receptor Protein-Tyrosine Kinases - physiology; Recombinant Fusion Proteins - biosynthesis; Rodents; Transcription Factors - biosynthesis; Transfection; Tumors; Zinc Fingers
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.15.7933

Germ-line missense mutations of the receptor-like tyrosine kinase ret are the causative genetic event of the multiple endocrine neoplasia (MEN) type 2A and type 2B syndromes and of the familial medullary thyroid carcinoma. We have used the rat pheochromocytoma cell line, PC12, as a model system to investigate the mechanism or mechanisms by which expression of activated ret alleles contributes to the neoplastic phenotype in neuroendocrine cells. Here we show that stable expression of ret mutants (MEN2A and MEN2B alleles) in PC12 cells causes a dramatic conversion from a round to a flat morphology, accompanied by the induction of genes belonging to the early as well as the delayed response to nerve growth factor. However, in the transfected PC12 cells, the continuous expression of neuronal specific genes is not associated with the suppression of cell proliferation. Furthermore, expression of ret mutants renders PC12 cells unresponsive to nerve growth factor-induced inhibition of proliferation. These results suggest that induction of an aberrant pattern of differentiation, accompanied by unresponsiveness to growth-inhibitory physiological signals, may be part of the mechanism of action of activated ret alleles in the pathogenesis of neuroendocrine tumors associated with MEN2 syndromes.