Identification of a novel NOTCH-4/INT-3 RNA species encoding an activated gene product in certain human tumor cell lines
Identification of a novel NOTCH-4/INT-3 RNA species encoding an activated gene product in certain human tumor cell lines
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DOI：
10.1038/sj.onc.1203295
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发表时间：
2000-01-13
期刊：
影响因子：
8
通讯作者：
Callahan, R
中科院分区：
文献类型：
--
作者：
Imatani, A;Callahan, R
NOTCH-4/INT-3胞内结构域的异位表达导致小鼠乳腺肿瘤发生。这是由功能获得性突变引起的。为了评估人类癌症中的功能获得性NOTCH-4/INT-3活性，我们调查了人类乳腺癌、肺癌和结肠癌组织培养细胞系中NOTCH-4/INT-3 RNA表达增加的证据。在正常人睾丸中检测到高水平的1.8 Kb NOTCH-4/INT-3 RNA种类，但在6.5 Kb种类普遍存在的其他组织中未检测到。转化的人癌细胞系表达1.8 Kb NOTCH-4/INT-3 RNA种类。我们发现，这种RNA种类编码NOTCH-4/INT-3胞内结构域（ICD）的截短形式。这种新的NOTCH-4/ INT-3蛋白包括CDC 10重复序列和它们的C-末端的氨基酸残基，但缺少NOTCH-4/INT-3 ICD的CBF-1结合区域，这表明它具有不同的作用模式。我们表明，在“正常”人乳腺上皮细胞系MCF-10A中表达1.8KbNOTCH-4/INT-3RNA种类的转基因使这些细胞能够在软琼脂中生长。
Ectopic expression of the intracellular domain of NOTCH-4/INT-3 leads to tumorigenesis in the mouse mammary gland. This results from a gain-of-function mutation. To evaluate gain-of-function NOTCH-4/INT-3 activity in human cancers we have surveyed human breast, lung, and colon carcinoma tissue culture cell lines for evidence of increased NOTCH-4/INT-3 RNA expression. High levels of a 1.8 Kb NOTCH-4/INT-3 RNA species are detected in normal human testis but not in other tissues where a 6.5 Kb species is prevalent. Transformed human cancer cell lines express the 1.8 Kb NOTCH-4/INT-3 RNA species. We show that this RNA species encodes a truncated form of the NOTCH-4/INT3 intracellular domain (ICD), This novel NOTCH-4/ INT-3 protein includes the CDC10 repeats and amino acid residues C-terminal to them, but is missing the CBF-1 binding region of the NOTCH-4/INT-3 ICD, This suggests that it has a different mode of action, Furthermore, we show that a transgene which expresses the 1.8 Kb NOTCH-4/INT-3 RNA species in the 'normal' human mammary epithelial cell line MCF-10A enables these cells to grow in soft agar.