NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth
NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth
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DOI：
10.1073/pnas.0606108103
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发表时间：
2006-11-28
影响因子：
11.1
通讯作者：
Ferrando, Adolfo A.
中科院分区：
文献类型：
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作者：
Palomero, Teresa;Lim, Wei Keat;Ferrando, Adolfo A.
NOTCH 1信号通路直接将细胞外信号与细胞核中的转录反应联系起来，并在T细胞发育过程中和超过50%的人类T细胞淋巴细胞白血病（T-ALL）病例的发病机制中发挥关键作用。然而，人们对NOTCH 1激活的转录程序知之甚少。使用综合系统生物学方法，我们表明，NOTCH 1控制一个前馈环转录网络，促进细胞生长。抑制TALL细胞中的NOTCH 1信号传导导致细胞大小减小，并引发由下调的生物合成途径基因主导的基因表达特征。通过整合基因表达阵列和ChIP芯片数据，我们发现NOTCH 1直接激活多种生物合成途径并诱导c-MYC基因表达。从表达谱的调控网络的逆向工程显示，NOTCH 1和c-MYC管理两个直接相互关联的转录程序，包含共同的靶基因，共同调节原代T-ALL细胞的生长。这些结果鉴定了c-MYC作为NOTCH 1信号传导的重要介质，并将NOTCH 1活化与c-MYC上游的致癌信号传导途径整合。
The NOTCH1 signaling pathway directly links extracellular signals with transcriptional responses in the cell nucleus and plays a critical role during T cell development and in the pathogenesis over 50% of human T cell lymphoblastic leukemia (T-ALL) cases. However, little is known about the transcriptional programs activated by NOTCH1. Using an integrative systems biology approach we show that NOTCH1 controls a feed-forward-loop transcriptional network that promotes cell growth. Inhibition of NOTCH1 signaling in TALL cells led to a reduction in cell size and elicited a gene expression signature dominated by down-regulated biosynthetic pathway genes. By integrating gene expression array and ChIP-on-chip data, we show that NOTCH1 directly activates multiple biosynthetic routes and induces c-MYC gene expression. Reverse engineering of regulatory networks from expression profiles showed that NOTCH1 and c-MYC govern two directly interconnected transcriptional programs containing common target genes that together regulate the growth of primary T-ALL cells. These results identify c-MYC as an essential mediator of NOTCH1 signaling and integrate NOTCH1 activation with oncogenic signaling pathways upstream of c-MYC.