The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways
The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways
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DOI：
10.1038/sj.cdd.4402057
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发表时间：
2007-05-01
影响因子：
12.4
通讯作者：
Stein, R.
中科院分区：
文献类型：
--
作者：
Shapira, S.;Barkan, B.;Stein, R.
1 型神经纤维瘤病 (NF1) 的特点是由于 Nf1 功能丧失而导致良性和恶性肿瘤的高发病率，Nf1 编码神经纤维蛋白，一种具有 Ras-GAP 活性的肿瘤抑制因子。神经纤维蛋白缺乏通常会导致 Ras 慢性激活，Ras 被认为是导致 NF1 表现的主要因素。对放疗和化疗的耐药性是 NF1 相关肿瘤的典型特征，但其潜在机制尚不清楚。在这里，我们研究了神经纤维蛋白表达、Ras 活性和细胞凋亡敏感性之间的相互关系。缺乏神经纤维蛋白的小鼠胚胎成纤维细胞 (MEF) 和人 NF1 肿瘤细胞比表达神经纤维蛋白的细胞更能抵抗细胞凋亡。此外，Nf1(-/-)、Nf1(+/-)和Nf1(+/+) MEF表现出基因剂量相关的细胞凋亡抗性。 Nf1 缺陷细胞的抵抗力是由两种生存途径介导的：Ras 依赖性途径，以及因神经纤维蛋白缺乏 NF1-GRD 独立促凋亡作用而促进的 Ras 独立途径。因此，除了 Ras 依赖性生长抑制作用外，神经纤维蛋白还可通过促凋亡作用发挥肿瘤抑制作用。
Neurofibromatosis type 1 (NF1) is characterized by a high incidence of benign and malignant tumors attributed to loss of function of Nf1, which encodes neurofibromin, a tumor suppressor with Ras-GAP activity. Neurofibromin deficiency typically causes chronic activation of Ras, considered the major contributor to manifestation of NF1. Resistance to radio- and chemotherapy are typical of NF1-associated tumors, but the underlying mechanism is unknown. Here, we investigated interrelationships between neurofibromin expression, Ras activity, and sensitivity to apoptosis. Neurofibromin-deficient mouse embryonic fibroblasts (MEFs) and human NF1 tumor cells were more resistant than neurofibromin-expressing cells to apoptosis. Moreover, Nf1(-/-) , Nf1(+/-), and Nf1(+/+) MEFs exhibited gene-dosage-related resistance to apoptosis. Resistance of the Nf1-deficient cells was mediated by two survival pathways: a Ras-dependent pathway, and a Ras-independent pathway promoted by the lack of an NF1-GRD- independent proapoptotic action of neurofibromin. Therefore, besides its Ras-dependent growth inhibition, neurofibromin can exert tumor suppression via a proapoptotic effect.