Neoplastic transformation by Notch requires nuclear localization
Neoplastic transformation by Notch requires nuclear localization
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DOI：
10.1128/mcb.20.11.3928-3941.2000
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发表时间：
2000-06-01
影响因子：
5.3
通讯作者：
Capobianco, AJ
中科院分区：
文献类型：
--
作者：
Jeffries, S;Capobianco, AJ
Notch蛋白是介导重要细胞命运决定如分化、增殖和凋亡的跨质膜受体。Notch信号传导的机制仍然知之甚少。然而，很明显，Notch信号通路通过相邻细胞之间的细胞间接触介导其作用。Notch信号传导的流行模型表明，存在于邻近细胞上的配体触发Notch的蛋白水解加工。在蛋白水解之后，认为Notch（N-ic）的细胞内部分易位到细胞核，在那里它参与调节基因表达。关于Notch在细胞中的功能以及哪些蛋白质作为Notch信号的效应物存在相当大的争论。几个Notch基因已清楚地显示为哺乳动物细胞中的原癌基因。Notch原癌基因的激活与几种人类和其他哺乳动物癌症的肿瘤发生有关。Notch的转化等位基因指导主要由N-ic组成并且不束缚于质膜的截短蛋白的表达。然而，Notch癌蛋白（这里统称为NLE）诱导肿瘤转化的机制尚不清楚。我们以前在体外证明了N1（ic）和N2（ic）可以转化E1 A永生化的幼鼠肾细胞（RKE）。我们现在报告的直接证据表明，N1（IC）必须积累在细胞核中，以诱导转化的RKE细胞。此外，我们定义了N1（IC）诱导转化所需的最小结构域，并提供证据表明N1（IC）对RKE细胞的转化可能是通过CBF 1独立途径。
Notch proteins are plasma membrane-spanning receptors that mediate important cell fate decisions such as differentiation, proliferation, and apoptosis. The mechanism of Notch signaling remains poorly understood. However, it is clear that the Notch signaling pathway mediates its effects through intercellular contact between neighboring cells. The prevailing model for Notch signaling suggests that ligand, presented on a neighboring cell, triggers proteolytic processing of Notch. Following proteolysis, it is thought that the intracellular portion of Notch (N-ic) translocates to the nucleus, where it is involved in regulating gene expression. There is considerable debate concerning where in the cell Notch functions and what proteins serve as effecters of the Notch signal. Several Notch genes have clearly been shown to be proto-oncogenes in mammalian cells. Activation of Notch proto-oncogenes has been associated with tumorigenesis in several human and other mammalian cancers. Transforming alleles of Notch direct the expression of truncated proteins that primarily consist of N-ic and are not tethered to the plasma membrane. However, the mechanism by which Notch oncoproteins (generically termed here as NLE) induce neoplastic transformation is not known. Previously we demonstrated that N1(ic) and N2(ic) could transform E1A immortalized baby rat kidney cells (RKE) in vitro. We now report direct evidence that N1(ic) must accumulate in the nucleus to induce transformation of RKE cells. In addition, we define the minimal domain of N1(ic) required to induce transformation and present evidence that transformation of RKE cells by N1(ic) is likely to be through a CBF1-independent pathway.