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首页> 外文期刊>Cell cycle >MDM2 as a critical effector of the MYCN oncogene in tumorigenesis.
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MDM2 as a critical effector of the MYCN oncogene in tumorigenesis.

机译：MDM2作为MYCN癌基因在肿瘤发生中的关键效应物。

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The MYCN oncogene plays an important role in the pathogenesis of neuroblastoma. It is amplified in more than 30% of high-risk cases and over expression induces neuroblastoma in transgenic mice. MYCN amplification/overexpression is found in many types of cancers including neuroblastoma, medulloblastoma and other aggressive tumors of neuroectodermal origin as well as in rhadomyosarcoma and small cell lung cancers. MYCN exerts its oncogenic effects through transcriptional regulation of numerous target genes. We have recently characterized the p53 inhibitor MDM2 (HDM2) as one such target in MYCN amplified neuroblastoma cell lines. Conditional expression of MYCN yields elevated MDM2 mRNA and protein. MYCN inhibition leads to diminished MDM2, stabilized p53 and apoptosis. As the primary negative regulator of p53, MDM2 is critically regulated in normal cells to ensure adequate p53 activity in response to damage or stress. Additionally, MDM2 regulates many p53 independent processes pertinent to oncogenesis. Wepropose that increased MDM2 levels downstream of MYCN are tumorigenic secondary to disruption of multiple p53 dependent and independent mechanisms controlling genomic stability, apoptopsis and cell cycle progression. Further research into the MYCN/MDM2 regulated pathways will provide insight into the pathogenesis of MYCN-driven tumors and provide targets for novel therapeutic interventions.
机译：MYCN癌基因在神经母细胞瘤的发病机理中起重要作用。在超过30％的高危病例中，它会被扩增，并且过表达会在转基因小鼠中诱导神经母细胞瘤。 MYCN扩增/过表达存在于许多类型的癌症中，包括神经母细胞瘤，髓母细胞瘤和其他神经外胚层起源的侵袭性肿瘤，以及横纹肌肉瘤和小细胞肺癌。 MYCN通过许多靶基因的转录调控发挥其致癌作用。我们最近已将p53抑制剂MDM2（HDM2）表征为MYCN扩增的神经母细胞瘤细胞系中的此类靶标之一。 MYCN的条件表达产生提高的MDM2 mRNA和蛋白。 MYCN抑制导致MDM2减少，p53稳定和凋亡。作为p53的主要负调节剂，MDM2在正常细胞中受到严格调节，以确保响应损伤或应激而具有足够的p53活性。另外，MDM2调节与肿瘤发生有关的许多p53独立过程。我们提出，MYCN下游MDM2水平的升高是继发于控制基因组稳定性，凋亡和细胞周期进程的多个p53依赖和独立机制破坏的致瘤因素。对MYCN / MDM2调控途径的进一步研究将提供对MYCN驱动的肿瘤发病机理的见识，并为新型治疗干预提供靶标。

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