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首页> 外文期刊>Molecular and Cellular Biology >Neoplastic Transformation by Notch Requires Nuclear Localization
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Neoplastic Transformation by Notch Requires Nuclear Localization

机译：缺口的肿瘤转化需要核定位

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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 (Nic) 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 effectors 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 Nic and are not tethered to the plasma membrane. However, the mechanism by which Notch oncoproteins (generically termed here as Nic) induce neoplastic transformation is not known. Previously we demonstrated that N1ic and N2iccould transform E1A immortalized baby rat kidney cells (RKE) in vitro. We now report direct evidence that N1ic must accumulate in the nucleus to induce transformation of RKE cells. In addition, we define the minimal domain of N1ic required to induce transformation and present evidence that transformation of RKE cells by N1ic is likely to be through a CBF1-independent pathway.
机译：Notch蛋白是跨膜的受体，介导重要的细胞命运决定，例如分化，增殖和凋亡。 Notch信号传导的机制仍知之甚少。但是，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，存在于相邻细胞上的配体会触发Notch的蛋白水解过程。进行蛋白水解后，人们认为Notch的细胞内部分（N ic ）易位至细胞核，并参与调节基因表达。关于Notch在细胞中的何处起作用以及哪些蛋白质充当Notch信号的效应物，存在大量争论。几个Notch基因已明确显示是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截短蛋白的表达，该蛋白主要由N ic 组成，不被束缚在质膜上。但是，Notch癌蛋白（在此通常称为N ic ）诱导肿瘤转化的机制尚不清楚。先前，我们证明了N1 ic 和N2 ic 可以在体外转化永生化的E1A幼鼠肾细胞（RKE）。我们现在报告直接证据，表明N1 ic 必须在细胞核中蓄积才能诱导RKE细胞转化。此外，我们定义了诱导转化所需的N1 ic 的最小域，并提供证据表明通过N1 ic 转化RKE细胞很可能是通过CBF1独立途径。

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