Mastermind-Like 3 Controls Proliferation and Differentiation in Neuroblastoma
Mastermind-Like 3 Controls Proliferation and Differentiation in Neuroblastoma
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DOI：
10.1158/1541-7786.mcr-15-0291-t
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发表时间：
2016-05-01
影响因子：
5.2
通讯作者：
Bajpe, Prashanth Kumar
中科院分区：
文献类型：
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作者：
Heynen, Guus J. J. E.;Nevedomskaya, Ekaterina;Bajpe, Prashanth Kumar
神经母细胞瘤细胞系在用视黄酸（RA）治疗后可以分化，这一发现为临床使用 RA 治疗神经母细胞瘤提供了基础。然而，经常观察到对 RA 的耐药性，这限制了其临床应用。通过功能获得性遗传筛选，我们发现了 RA 信号传导与 mastermind-like 3 (MAML3)（一种已知的 NOTCH 转录共激活因子）之间存在意想不到的联系。我们的研究结果表明，MAML3 表达导致 RA 靶基因子集失去激活，从而阻碍 RA 诱导的分化并促进对 RA 的抵抗。这组 RA 靶基因的调节 DNA 元件在 MAML3 和 RA 受体的结合中显示出重叠，表明 MAML3 在这些基因的调节中具有直接作用。此外，MAML3 具有不依赖于 RA 的功能，包括通过上调 IGF2 激活 IGF1R 和下游 AKT 信号传导，从而导致增殖增加。这些结果证明了 MAML3 在增殖和 RA 介导的分化中的重要机制作用。意义：MAML3 协调转录调控与受体酪氨酸激酶通路激活，为解释该基因在多种癌症中发生突变的原因提供了新的线索。
Neuroblastoma cell lines can differentiate upon treatment with retinoic acid (RA), a finding that provided the basis for the clinical use of RA to treat neuroblastoma. However, resistance to RA is often observed, which limits its clinical utility. Using a gain-of-function genetic screen, we identified an unexpected link between RA signaling and mastermind-like 3 (MAML3), a known transcriptional coactivator for NOTCH. Our findings indicate that MAML3 expression leads to the loss of activation of a subset of RA target genes, which hampers RA-induced differentiation and promotes resistance to RA. The regulatory DNA elements of this subset of RA target genes show overlap in binding of MAML3 and the RA receptor, suggesting a direct role for MAML3 in the regulation of these genes. In addition, MAML3 has RA-independent functions, including the activation of IGF1R and downstream AKT signaling via upregulation of IGF2, resulting in increased proliferation. These results demonstrate an important mechanistic role for MAML3 in proliferation and RA-mediated differentiation.Implications: MAML3 coordinates transcription regulation with receptor tyrosine kinase pathway activation, shedding new light on why this gene is mutated in multiple cancers.