Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
Exp Cell Res. 2010 May 15;316(9):1610-24. doi: 10.1016/j.yexcr.2009.12.012. Epub 2009 Dec 23.
Interaction between key signaling mechanisms is important to generate the diversity in signaling output required for proper control of cellular differentiation and function, although the molecular manifestations of such cross-talk are only partially understood. Notch signaling and the cellular response to hypoxia intersect at different points in the signaling cascades, and in this report we analyze the consequences of this cross-talk at the transcriptome level. Mouse ES cells were subjected to various combinations of hypoxia and/or activated Notch signaling, and the transcriptome changes could be grouped into different categories, reflecting various modes of hypoxia and Notch signaling integration. Two principal categories of novel Notch- and hypoxia-induced genes were identified: (i) a larger set of Notch or hypoxic target genes which were induced by one pathway and not significantly affected by the activity status of the other pathway and (ii) a smaller set of genes co-regulated by Notch and hypoxia. In the latter category, we identified genes that were induced by hypoxia and the expression of which was enhanced by active Notch signaling and another group of genes that were induced by Notch and hypoxia independently. Several of the hypoxia- and Notch-induced genes were found to be upregulated in various forms of cancer. Identification of genes co-regulated by the two pathways may provide a molecular platform to better understand the intersection between the two signaling cascades in normal development and cancer.
信号转导机制之间的相互作用对于产生细胞分化和功能所需的信号输出多样性非常重要，尽管这种串扰的分子表现形式仅部分被理解。Notch 信号转导和细胞对缺氧的反应在信号级联的不同点相交，在本报告中，我们在转录组水平上分析了这种串扰的后果。将小鼠 ES 细胞暴露于缺氧和/或激活的 Notch 信号的各种组合中，转录组的变化可以分为不同的类别，反映了缺氧和 Notch 信号转导整合的各种模式。确定了两类新型 Notch 和缺氧诱导基因：（i）一组较大的 Notch 或缺氧靶基因，它们被一条途径诱导，而不受另一条途径活性状态的显著影响；（ii）一组由 Notch 和缺氧共同调控的较小基因。在后一类中，我们鉴定了由缺氧诱导的基因，其表达受活性 Notch 信号增强，以及另一组由 Notch 和缺氧独立诱导的基因。几种缺氧和 Notch 诱导的基因在各种形式的癌症中被发现上调。鉴定由两条途径共同调控的基因可能为更好地理解两个信号级联在正常发育和癌症中的交汇提供分子平台。
