SOMATIC MUTATIONS IN THE NEUROFIBROMATOSIS-1 GENE IN HUMAN TUMORS
SOMATIC MUTATIONS IN THE NEUROFIBROMATOSIS-1 GENE IN HUMAN TUMORS
复制标题
DOI：
10.1016/0092-8674(92)90408-5
复制
发表时间：
1992-04-17
期刊：
影响因子：
64.5
通讯作者：
CAWTHON, R
中科院分区：
文献类型：
--
作者：
LI, Y;BOLLAG, G;CAWTHON, R
神经纤维瘤病1(NF1)基因产物神经纤维素含有GTP酶激活蛋白(GAP)相关结构域，或NF1 GRD，它能通过刺激其固有的GTP酶下调p21ras。由于p21ras-GTP是生长和分化的主要调节因子，NF1基因体细胞突变导致的突变型神经纤维蛋白可能干扰ras信号通路，促进肿瘤的发展。我们描述了NF1 GRD中的一个氨基酸替换，改变了Lys-1423，它发生在三种肿瘤类型：结肠腺癌、骨髓增生异常综合征和间变性星形细胞瘤，以及一个神经纤维瘤病1家系。突变的NF1 GRD的GAP活性比野生型低200-400倍，而结合亲和力没有受到影响。因此，导致神经纤维瘤病1的NF1胚系突变也可以发生在体细胞中，并有助于零星肿瘤的发展，包括与神经纤维瘤病1无关的肿瘤。
The neurofibromatosis 1 (NF1) gene product, neurofibromin, contains a GTPase-activating protein (GAP)-related domain, or NF1 GRD, that is able to down-regulate p21ras by stimulating its intrinsic GTPase. Since p21ras-GTP is a major regulator of growth and differentiation, mutant neurofibromins resulting from somatic mutations in the NF1 gene might interfere with ras signaling pathways and contribute to the development of tumors. We describe an amino acid substitution in the NF1 GRD, altering Lys-1423, that has occurred in three tumor types: colon adenocarcinoma, myelodysplastic syndrome, and anaplastic astrocytoma, and in one family with neurofibromatosis 1. The GAP activity of the mutant NF1 GRD is 200- to 400-fold lower than that of wild type, whereas binding affinity is unaffected. Thus, germline mutations in NF1 that cause neurofibromatosis 1 can also occur in somatic cells and contribute to the development of sporadic tumors, including tumors not associated with neurofibromatosis 1.