C-MYC Targets in the Pathogenesis of Human Cancer

描述（由申请人提供）：c-Myc致癌转录因子通过调控基因表达在许多人类癌症中起关键作用。尽管Myc调控基因表达的方式已经得到了更好的定义，但Myc调控的基因群只是从各种不同的实验方法中出现的。通过使用减法克隆、DMA微阵列分析、SAGE、ChIP和基因组标记方法，Myc靶基因的大型数据集补充了个体Myc靶基因及其功能含义的研究。我们在Myc靶基因数据库（www.myccancergene.org）中对这些数据进行了注释。Myc靶基因似乎以一种依赖于环境的方式对Myc作出反应。特别是，其他转录因子如何与Myc协同调节这些基因以及细胞类型特异性作用需要进一步研究。为了充分了解肿瘤中Myc生理功能和不受调节的Myc功能之间的差异，挑战在于描述Myc应答转录组如何影响Myc诱导的各种表型。具体来说，我们假设在生理条件下，Myc与特定的转录因子合作促进基因表达，而在病理性的Myc高表达下，Myc能够诱导一组不同的异位Myc靶基因，这些基因有助于肿瘤的发生。为了达到了解Myc在人类癌症中的长期目标，我们设定了以下具体目标：确定生理和病理Myc靶基因网络的差异，并确定编码转录因子和其他关键信号转导蛋白的下游靶枢纽。目标2。维护和完善Myc靶基因数据库。目标3。鉴定与Myc协同调控下游靶标的转录因子。目标4。确定Myc与缺氧诱导转录因子HIF1协同调节对肿瘤生存至关重要的缺氧反应基因（如编码糖酵解酶的基因）的分子机制。

DESCRIPTION (provided by applicant): The c-Myc oncogenic transcription factor plays a key role in many human cancers through the regulation of gene expression. Although how Myc regulates gene expression is better defined, the groups of genes that Myc regulate are just emerging from a variety of different experimental approaches. Studies of individual Myc target genes and their functional implications are now complemented by large datasets of Myc target genes through the use of subtraction cloning, DMA microarray analysis, SAGE, ChIP, and genome marking methods. We have annotated these data in a Myc Target Gene database (www.myccancergene.org). Myc target genes appear to respond to Myc in a context dependent manner. In particular, how other transcription factors collaborate with Myc to regulate these genes as well as cell type specific effects need further study. To fully appreciate the differences between physiological Myc function and deregulated Myc function in tumors, the challenge is to delineate how the Myc-responsive transcriptomes influence the various phenotypes induced by Myc. Specifically, we hypothesize that under physiological conditions, Myc cooperates with specific transcription factors to promote gene expression, while under pathological, high Myc expression, Myc is able to induced a distinct set of ectopic Myc target genes that contribute to tumorigenesis. To reach our long-term goal of understanding Myc in human cancers we set the following Specific Aims: Aim 1. To determine differences between the physiological and pathological Myc target gene networks and identify downstream target hubs that encode transcription factors and other key signal transduction proteins. Aim 2. To maintain and improve the Myc target gene database. Aim 3. To identify transcription factors that cooperate with Myc in regulating downstream targets. Aim 4. To determine the molecular mechanisms by which Myc collaborates with the hypoxia inducible transcription factor, HIF1, in regulating hypoxia-responsive genes vital for tumor survival such as those encoding glycolytic enzymes.