Function and Regulation of the ETS Transcriptional Repressor Tel-1/YAN

好了！ 项目总结 这是一份关于1R01GM080372“ETS功能和监管的续展申请的修订提案 转录抑制因子TEL1/Yen“。 发育程序是由转录因子驱动的，转录因子协调基因的精确模式 对诱导信号提示做出反应的表达。这项提案的目标是揭示监管机构 使祖代的基因表达程序保持稳定，但又准备快速和精确的策略 对启动细胞命运指定的诱导信号做出反应的激活。具体地说，我们将研究 转录因子Ets家族中两个保守成员的作用：抑制子Yan和激活子 POINT(PNT)，在人类中称为TEL1/ETV6和ETS1/ETS2，协调从祖细胞到 受体酪氨酸激酶/RAS/MAPK信号通路对细胞命运的影响。中环 假设所指向的激活器首先组织和协调整个事件序列 与阎学通合作建立了最初的压抑状态，然后对立地切换到 系统通过激活基因表达和采用细胞命运。目标1探索不同的目标如何指向 亚型决定了系统对MAPK信号的敏感性和反应。目标2将阐明分子 在细胞命运指定过程中协调POINT作为抑制者和激活者的双重角色的机制 进程。因为我们正在测试的想法涉及发育调节的基本机制，并且 我们研究的信号因子和转录网络是保守的，新出现的发现将 有广泛的影响。

! PROJECT SUMMARY This is a revised proposal for a renewal application for 1R01GM080372 "Function and regulation of the ETS transcriptional repressor TEL1/Yan". Developmental programs are driven by transcription factors that coordinate precise patterns of gene expression in response to inductive signaling cues. The goals of this proposal are to uncover the regulatory strategies that keep gene expression programs in progenitors stably off, yet poised for rapid and precise activation in response to the inductive cues that initiate cell fate specification. Specifically we will study how the action of two members of the conserved ETS family of transcription factors, a repressor Yan and an activator Pointed (Pnt), known as TEL1/ETV6 and ETS1/ETS2 in humans, orchestrates the transition from progenitor to specified cell fate in response to receptor tyrosine kinase/Ras/MAPK signaling pathway. The central hypothesis is that the activator Pointed organizes and coordinates the entire sequence of events by first cooperating with Yan to establish the initial repressed state and then working in opposition to switch the system over to activation of gene expression and adoption of cell fate. Aim 1 explores how different Pointed isoforms determine the system's sensitivity and response to MAPK signaling. Aim 2 will elucidate the molecular mechanisms that coordinate Pointed's dual roles as repressor and activator during the cell fate specification process. Because the ideas we are testing address fundamental mechanisms of developmental regulation, and the signaling factors and transcriptional networks we study are conserved, the discoveries that emerge will have broad impact.