MYCN-mediated transcriptional repression in neuroblastoma: the other side of the coin.
MYCN-mediated transcriptional repression in neuroblastoma: the other side of the coin.
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DOI：
10.3389/fonc.2013.00042
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发表时间：
2013
影响因子：
4.7
通讯作者：
Perini G
中科院分区：
文献类型：
--
作者：
Gherardi S;Valli E;Erriquez D;Perini G
神经母细胞瘤是儿童最常见的颅外实体肿瘤，也是婴儿期诊断最多的肿瘤。MYCN扩增和过度表达约占神经母细胞瘤总数的25%，在晚期神经母细胞瘤中这一比例增加了30%。到目前为止，MYCN表达谱仍然是神经母细胞瘤预后最可靠和最重要的预后指标之一。MYCN是一种属于MYC癌蛋白家族的转录因子，由c-MYC和MYCL基因组成。MYC癌蛋白表达的失控是不同类型恶性肿瘤发生的关键事件。MYCN和c-MYC可以与其伴侣MAX发生异源二聚反应，激活启动子区域含有E-Box位点的几个靶基因的转录。然而，最近的几条证据表明，MYCN至少可以抑制和激活一样多的基因，从而提出了该蛋白在神经母细胞瘤生物学中的一种新功能。虽然MYCN作为转录激活剂的作用机制是众所周知的，但很少有研究试图解释MYCN如何发挥其转录抑制功能。在这里，我们将回顾关于MYCN介导的转录抑制机制的现有知识，并将强调其在招募一组精确的蛋白质以形成能够下调特定基因亚组的复合体中的作用，这些复合体的功能积极参与细胞凋亡、细胞分化、化疗敏感性和细胞运动。MYCN还可以作为抑制因子，这一发现拓宽了我们对其在肿瘤发生中作用的认识，并为寻找针对其转录抑制功能的新型治疗药物奠定了基础。
Neuroblastoma is the most common extra cranial solid tumor in childhood and the most frequently diagnosed neoplasm during the infancy. MYCN amplification and overexpression occur in about 25% of total neuroblastoma cases and this percentage increases at 30% in advanced stage neuroblastoma. So far, MYCN expression profile is still one of the most robust and significant prognostic markers for neuroblastoma outcome. MYCN is a transcription factor that belongs to the family of MYC oncoproteins, comprising c-MYC and MYCL genes. Deregulation of MYC oncoprotein expression is a crucial event involved in the occurrence of different types of malignant tumors. MYCN, as well as c-MYC, can heterodimerize with its partner MAX and activate the transcription of several target genes containing E-Box sites in their promoter regions. However, recent several lines of evidence have revealed that MYCN can repress at least as many genes as it activates, thus proposing a novel function of this protein in neuroblastoma biology. Whereas the mechanism by which MYCN can act as a transcriptional activator is relatively well known, very few studies has been done in the attempt to explain how MYCN can exert its transcription repression function. Here, we will review current knowledge about the mechanism of MYCN-mediated transcriptional repression and will emphasize its role as a repressor in the recruitment of a precise set of proteins to form complexes capable of down-regulating specific subsets of genes whose function is actively involved in apoptosis, cell differentiation, chemosensitivity, and cell motility. The finding that MYCN can also act as a repressor has widen our view on its role in oncogenesis and has posed the bases to search for novel therapeutic drugs that can specifically target its transcriptional repression function.