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
Instituto Nazionale dei Tumori Fondazione G Pascale, Napoli, Italy.
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7933-7. 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.
受体样酪氨酸激酶ret的生殖系错义突变是2A型和2B型多发性内分泌腺瘤（MEN）综合征以及家族性甲状腺髓样癌的致病遗传事件。我们使用大鼠嗜铬细胞瘤细胞系PC12作为模型系统，来研究激活的ret等位基因的表达促成神经内分泌细胞肿瘤表型的一种或多种机制。在此我们表明，PC12细胞中ret突变体（MEN2A和MEN2B等位基因）的稳定表达导致细胞形态从圆形急剧转变为扁平形，同时伴随着属于对神经生长因子早期和延迟反应的基因的诱导。然而，在转染的PC12细胞中，神经元特异性基因的持续表达与细胞增殖的抑制无关。此外，ret突变体的表达使PC12细胞对神经生长因子诱导的增殖抑制无反应。这些结果表明，异常分化模式的诱导，伴随着对生长抑制性生理信号的无反应，可能是激活的ret等位基因在与MEN2综合征相关的神经内分泌肿瘤发病机制中的作用机制的一部分。
