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

ETS转录抑制子的功能和调控Tel-1/YAN

基本信息

批准号：
10251048
负责人：
Ilaria Rebay
金额：
$ 35.12万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251048
关键词：
Address Adoption Biological Models Biological Process Cell physiology Cells Chromatin Complex Cues DNA Binding Defect Development Drosophila genus ETS1 gene ETS2 gene ETV6 gene Embryo Enhancers Ensure Event Expression Profiling Family Gene Activation Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Goals Heterozygote Human Human Development Impairment Investigation Lead MAP Kinase Gene MAPK Signaling Pathway Pathway Mammals Mediating Mesoderm Modeling Molecular Multipotent Stem Cells Oncogenic Phenotype Phosphorylation Process Property Protein Isoforms Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Regulation Repression Role Signal Induction Signal Transduction Solid Neoplasm Specific qualifier value Specificity System TEL1 Gene Testing Tissues To specify Transcription Repressor Work base cell fate specification fly genetic corepressor genome-wide human disease improved interest leukemia member mutant prevent progenitor programs receptor response transcription factor

项目摘要

! 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.

！项目概要这是针对 1R01GM080372“ETS 的功能和监管”续期申请的修订提案转录抑制子TEL1/Yan”。发育程序由协调基因精确模式的转录因子驱动响应诱导信号线索的表达。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，但仍准备好快速、精确响应启动细胞命运规范的诱导线索而激活。具体来说，我们将研究如何保守的 ETS 转录因子家族的两个成员（阻遏物 Yan 和激活物）的作用 Pointed (Pnt)，在人类中被称为 TEL1/ETV6 和 ETS1/ETS2，协调从祖细胞到响应受体酪氨酸激酶/Ras/MAPK信号通路的特定细胞命运。中央假设激活器 Pointed 首先组织并协调整个事件序列与严合作建立最初的压制状态，然后与反对派合作以改变这种状态系统转变为基因表达的激活和细胞命运的采用。目标 1 探讨 Pointed 有何不同同种型决定系统对 MAPK 信号传导的敏感性和响应。目标 2 将阐明分子在细胞命运规范过程中协调 Pointed 作为抑制子和激活子的双重角色的机制过程。因为我们正在测试的想法涉及发育调节的基本机制，并且我们研究的信号因子和转录网络是保守的，出现的发现将具有广泛的影响。