D'Alessio A, De Vita G, Calì G, Nitsch L, Fusco A, Vecchio G, Santelli G, Santoro M, de Franciscis V
Endocrinology and Experimental Oncology Center, Consiglio Nazionale delle Ricerche, Italy.
Cell Growth Differ. 1995 Nov;6(11):1387-94.
Expression of the RET proto-oncogene, a cell surface receptor for an as yet unknown ligand, is associated with tumors, tissues, and cell lines of neural crest origin. Accumulating evidence suggests that RET activity is involved in the process of neuronal differentiation. Moreover, induction of phenotypic differentiation of neuroblastoma cell lines is associated with the rapid accumulation of RET transcripts. To verify the role of RET in neuronal differentiation, we introduced into the human neuroblastoma cell line SK-N-BE four versions of the RET oncogene, activated by different mechanisms: RET/PTC1 and RET/PTC3, which are activated by rearrangement with heterologous genes; and two activated RET mutants, which carry the single amino acid substitution found associated to the inheritance of the multiple endocrine neoplasia type 2A (retMEN2A allele) and type2B (retMEN2B allele), respectively. We demonstrate that, after transfection with the RET oncogenes, SK-N-BE cells display a reduced growth rate and acquire a neurite-bearing phenotype accompanied by enhanced expression of the axonal growth-associated protein, GAP-43, and the high molecular weight neurofilament, NF200. These results indicate that, when activated, RET is able to cause growth inhibition and to promote neuronal differentiation of neuroblastoma cells.
RET原癌基因是一种细胞表面受体，其配体尚不清楚，它的表达与神经嵴起源的肿瘤、组织及细胞系有关。越来越多的证据表明，RET活性参与神经元分化过程。此外，神经母细胞瘤细胞系的表型分化诱导与RET转录本的快速积累有关。为了验证RET在神经元分化中的作用，我们将四种通过不同机制激活的RET癌基因导入人神经母细胞瘤细胞系SK-N-BE：RET/PTC1和RET/PTC3，它们通过与异源基因重排而激活；以及两个激活的RET突变体，分别携带与2A型多发性内分泌肿瘤（retMEN2A等位基因）和2B型（retMEN2B等位基因）遗传相关的单氨基酸替代。我们证明，用RET癌基因转染后，SK-N-BE细胞生长速率降低，并获得带有神经突的表型，同时轴突生长相关蛋白GAP-43和高分子量神经丝NF200的表达增强。这些结果表明，激活后的RET能够抑制神经母细胞瘤细胞的生长并促进其神经元分化。
