INACTIVATION OF THE NF1 GENE IN HUMAN-MELANOMA AND NEUROBLASTOMA CELL-LINES WITHOUT IMPAIRED REGULATION OF GTP.RAS
INACTIVATION OF THE NF1 GENE IN HUMAN-MELANOMA AND NEUROBLASTOMA CELL-LINES WITHOUT IMPAIRED REGULATION OF GTP.RAS
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DOI：
10.1073/pnas.90.12.5539
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发表时间：
1993-06-15
影响因子：
11.1
通讯作者：
LOWY, DR
中科院分区：
文献类型：
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作者：
JOHNSON, MR;LOOK, AT;LOWY, DR
在1型神经纤维瘤病患者中改变的NF 1基因编码神经纤维蛋白，其GTP酶激活功能可以通过加速其转化为无活性GDP. Ras来负调节GTP.Ras。在神经纤维瘤病患者的神经鞘瘤细胞系中，神经纤维蛋白的丢失先前被证明与GTP-Ras调节受损相关。我们对其他神经嵴来源的肿瘤细胞系的分析表明，一些黑色素瘤和神经母细胞瘤细胞系，从发生在没有神经纤维瘤病的患者的肿瘤中建立，含有减少或检测不到的神经纤维蛋白水平，伴随着NF 1基因座的遗传异常。与神经鞘瘤细胞系相反，GTP.Ras在神经纤维蛋白缺乏的黑色素瘤和神经母细胞瘤细胞系中得到适当调节，即使c-H-ras在细胞系中过表达。这些结果表明，一些与神经纤维瘤病无关的神经嵴肿瘤获得了体细胞失活的NF 1基因，并建议神经纤维蛋白的肿瘤抑制功能是独立的Ras GT3激活。
The NF1 gene, which is altered in patients with type 1 neurofibromatosis, encodes neurofibromin, a protein whose GTPase-activating function can negatively regulate GTP.Ras by accelerating its conversion to inactive GDP.Ras. In schwannoma cell lines from patients with neurofibromatosis, loss of neurofibromin was previously shown to be associated with impaired regulation of GTP-Ras. Our analysis of other neural crest-derived tumor cell lines has shown that some melanoma and neuroblastoma cell lines established from tumors occurring in patients without neurofibromatosis contain reduced or undetectable levels of neurofibromin, with concomitant genetic abnormalities of the NF1 locus. In contrast to the schwannoma cell lines, GTP.Ras was appropriately regulated in the melanoma and neuroblastoma lines that were deficient in neurofibromin, even when c-H-ras was overexpressed in the lines. These results demonstrate that some neural crest tumors not associated with neurofibromatosis have acquired somatically inactivated NF1 genes and suggest a tumor-suppressor function for neurofibromin that is independent of Ras GTPase activation.