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

! 项目摘要 这是1 R 01 GM 080372“ETS的功能和管理”更新申请的修订提案 转录抑制因子TEL 1/Yan”。 发育程序是由转录因子驱动的，这些转录因子协调基因的精确模式。 表达对诱导信号线索的反应。该提案的目标是揭示监管 保持祖细胞中基因表达程序稳定关闭的策略， 细胞命运特异性是指细胞对诱导信号的应答激活。具体来说，我们将研究 转录因子保守ETS家族的两个成员，一个抑制子Yan和一个激活子的作用 人类称为TEL 1/ETV 6和ETS 1/ETS 2的Pointed（Pnt），协调了从祖细胞到 特异性细胞命运响应于受体酪氨酸激酶/Ras/MAPK信号通路。中央 一个假设是，激活器Pointed首先通过以下方式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，然后与阎学通对立， 基因表达的激活和细胞命运的通过。目标1探讨了如何不同的指向 同种型决定系统对MAPK信号传导的敏感性和响应。目的2将阐明分子 在细胞命运指定过程中协调Pointed作为阻遏物和激活物的双重作用的机制 过程因为我们正在测试的想法涉及发育调节的基本机制， 我们研究的信号因子和转录网络是保守的，这些发现将 具有广泛的影响。

! 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.