A potential pathogenetic mechanism for multiple endocrine neoplasia type 2 syndromes involves ret-induced impairment of terminal differentiation of neuroepithelial cells

D. Califano, A. D'Alessio, G. L. Colucci-D'Amato, G. De Vita, C. Monaco, G. Santelli, P. P. Di Fiore, G. Vecchio, A. Fusco, M. Santoro, V. De Franciscis

Research output: Contribution to journalArticle

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Abstract

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 uuresponsiveness 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.

Original languageEnglish
Pages (from-to)7933-7937
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number15
DOIs
Publication statusPublished - Jul 23 1996

Fingerprint

Neuroepithelial Cells
Multiple Endocrine Neoplasia Type 2a
Multiple Endocrine Neoplasia
PC12 Cells
Alleles
Nerve Growth Factor
Neuroendocrine Cells
Neuroendocrine Tumors
Germ-Line Mutation
Receptor Protein-Tyrosine Kinases
Missense Mutation
Genes
Cell Proliferation
Phenotype
Growth

Keywords

  • nerve growth factor
  • neuroendocrine
  • PC12
  • signal transduction
  • TRK

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

A potential pathogenetic mechanism for multiple endocrine neoplasia type 2 syndromes involves ret-induced impairment of terminal differentiation of neuroepithelial cells. / 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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 15, 23.07.1996, p. 7933-7937.

Research output: Contribution to journalArticle

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