Capobianco A J, Zagouras P, Blaumueller C M, Artavanis-Tsakonas S, Bishop J M
The George Williams Hooper Foundation, University of California, San Francisco, 94143-0552, USA.
Mol Cell Biol. 1997 Nov;17(11):6265-73. doi: 10.1128/MCB.17.11.6265.
The Notch genes of Drosophila melanogaster and vertebrates encode transmembrane receptors that help determine cell fate during development. Although ligands for Notch proteins have been identified, the signaling cascade downstream of the receptors remains poorly understood. In human acute lymphoblastic T-cell leukemia, a chromosomal translocation damages the NOTCH1 gene. The damage apparently gives rise to a constitutively activated version of NOTCH protein. Here we show that a truncated version of NOTCH1 protein resembling that found in the leukemic cells can transform rat kidney cells in vitro. The transformation required cooperation with the E1A oncogene of adenovirus. The transforming version of NOTCH protein was located in the nucleus. In contrast, neither wild-type NOTCH protein nor a form of the truncated protein permanently anchored to the plasma membrane produced transformation in vitro. We conclude that constitutive activation of NOTCH similar to that found in human leukemia can contribute to neoplastic transformation. Transformation may require that the NOTCH protein be translocated to the nucleus. These results sustain a current view of how Notch transduces a signal from the surface of the cell to the nucleus.
果蝇和脊椎动物的Notch基因编码跨膜受体，这些受体在发育过程中有助于确定细胞命运。尽管已经鉴定出Notch蛋白的配体，但受体下游的信号级联反应仍知之甚少。在人类急性淋巴细胞性T细胞白血病中，一种染色体易位会损害NOTCH1基因。这种损害显然会产生一种组成型激活的NOTCH蛋白。在此我们表明，一种类似于白血病细胞中发现的NOTCH1蛋白的截短形式能够在体外转化大鼠肾细胞。这种转化需要与腺病毒的E1A癌基因协同作用。具有转化作用的NOTCH蛋白位于细胞核中。相比之下，野生型NOTCH蛋白或一种永久锚定在质膜上的截短蛋白形式在体外均未产生转化作用。我们得出结论，类似于人类白血病中发现的NOTCH的组成型激活可能有助于肿瘤转化。转化可能需要NOTCH蛋白转运至细胞核。这些结果支持了目前关于Notch如何将信号从细胞表面转导至细胞核的观点。
