Ras pathway signals are required for notch-mediated oncogenesis
Ras pathway signals are required for notch-mediated oncogenesis
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DOI：
10.1038/sj.onc.1203766
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发表时间：
2000-08-31
期刊：
影响因子：
8
通讯作者：
Leder, P
中科院分区：
文献类型：
--
作者：
Fitzgerald, K;Harrington, A;Leder, P
线虫、线虫、黑腹果蝇和脊椎动物的Notch基因编码负责发育过程中细胞命运决定的受体。这些Notch受体及其配体Delta和Jagged与多种人类疾病有关。截短的，组成型活性突变形式的Notch受体似乎参与人类T细胞白血病，小鼠乳腺癌，和线虫的肿瘤生殖细胞表型。由于激活的Notch在转基因小鼠中诱导孤立性肿瘤，因此肿瘤形成极有可能需要协作遗传事件。我们评估了四种信号转导途径，以确定哪些可能与激活的Notch 4一起在恶性转化中发挥额外作用。我们的研究结果表明，由Notch的转化并不像预期的那样依赖于Src样激酶Lck和Fyn，也不依赖于来自蛋白激酶A和C（PKA，PKC）的信号。相反，通过Notch的转化需要来自Ras下游的Erk/MAP激酶和PI-3激酶途径的活性信号。
The Notch genes of C, elegans, Drosophila melanogaster and vertebrates encode receptors responsible for cell fate decisions during development. These Notch receptors and their ligands, Delta and Jagged, have been implicated in several human diseases. Truncated, constitutively active mutant forms of the Notch receptor appear to be involved in human T-cell leukemia, mammary carcinomas in mice, and a tumorous germline phenotype in C, elegans. Since activated Notch induces solitary tumors in transgenic mice, it is highly likely that collaborating genetic events are required for tumor formation, We have assessed four signal transduction pathways to determine which might play additional roles in malignant transformation in concert with activated Notch4. Our results suggest that transformation by Notch does not, as might have been expected, depend on the Src-like kinases Lck and Fyn, nor upon signals from protein kinase A and C (PKA, PKC). Rather, transformation by Notch requires active signals from the Erk/MAP kinase and PI-3 kinase pathways downstream of Ras.