Transcriptional Repression Mechanisms of COUP Proteins

COUP 蛋白的转录抑制机制

基本信息

批准号：
6636399
负责人：
MARK E LEID
金额：
$ 28.6万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2005-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6636399
关键词：
developmental genetics developmental neurobiology gene expression gene induction /repression genetic mapping genetic transcription heterochromatin laboratory mouse nuclear receptors protein protein interaction protein structure function transcription factor

项目摘要

DESCRIPTION: (Scanned from the applicant's abstract) Members of the COUP family of orphan nuclear receptors (COUP-TFI, ARP1 and Ear2) play crucial, yet poorly understood roles in fetal development, including neurogenesis and angiogenesis, and in homeostatic regulatory mechanisms in adult organisms. These proteins are generally believed to function as transcriptional repressors in a histone deacetylase-dependent pathway(s). We have recently identified a mechanistically novel pathway of COUP-mediated transcriptional repression that does not involve the action of trichostatin A-sensitive histone deacetylase(s). A key component in this pathway is the action of two novel, tissue-specifically expressed proteins, CTIP1 and CTIP2, both of which are C2H2 zinc finger proteins that interact directly with all COUP family members and recruit the orphan receptors to heterochromatic loci associated with transcriptional silencing. The CTIPs are also DNA binding proteins that repress transcription from CTIP response elements in mammalian cells independently of the COUP proteins. The CTIP proteins are of great biomedical interest not only because of their role in a novel COUP signaling mechanism, as bona fide transcription factors, and because the mouse CTIP1 locus was identified recently as a site of retroviral insertion that results in cellular transformation and leukemogenesis. The long-term goal of this laboratory is to elucidate the biological significance of and mechanisms by which CTIP proteins influence the transcriptional regulatory activity of COUP family members. To advance toward this goal, the objectives of this proposal are: (1) to determine the mechanistic basis for the action of CTIPs in transcriptional repression mediated by COUP family members, and (2) to determine the biological function(s) of the CTIP proteins. These objectives will be achieved in the context of four Specific Aims: (1) to elucidate the molecular basis of ARP1.CTIP1-mediated transcriptional repression, (2) to identify target genes regulated by CTIP proteins, (3) to elucidate the expression pattern of CTIPs in the developing mouse embryo and adult brain, (4) to determine the function of CTIPs in mice The research proposed in this application will have significant, positive effects on human health on two levels. Firstly, this work will expand our understanding of transcriptional repression mediated by the COUP proteins, possibly other members of the nuclear receptor superfamily, and a growing number of other transcription factors that repress transcription through histone deacetylase-independent pathways in health and disease. Secondly, this work will provide the cornerstone for understanding the molecular, cellular and organismal functions of the CTIP proteins, a novel class of transcriptional repressors that appear to play a pivotal role in the regulation of cellular proliferation in specific hematopoietic cell lineages.

描述：（从申请人的摘要中扫描）COUP 家族的成员孤儿核受体（COUP-TFI、ARP1 和 Ear2）发挥着至关重要的作用，但效果不佳了解胎儿发育中的作用，包括神经发生和血管发生，以及成体生物体的稳态调节机制。这些蛋白质是通常认为在组蛋白中充当转录抑制因子脱乙酰酶依赖性途径。我们最近从机械上确定了 COUP介导的转录抑制的新途径不涉及曲古抑菌素 A 敏感组蛋白脱乙酰酶的作用。关键部件在此途径中，有两种新颖的组织特异性表达的作用 CTIP1 和 CTIP2 蛋白，两者都是 C2H2 锌指蛋白，直接与所有 COUP 家族成员相互作用并招募孤儿受体与转录沉默相关的异染色质位点。 CTIP 也是抑制 CTIP 反应转录的 DNA 结合蛋白哺乳动物细胞中独立于 COUP 蛋白的元件。 CTIP 蛋白质具有巨大的生物医学意义，不仅因为它们在新颖的 COUP 信号传导机制，作为真正的转录因子，并且因为小鼠 CTIP1 位点最近被鉴定为逆转录病毒插入位点导致细胞转化和白血病发生。该实验室的长期目标是阐明生物学 CTIP蛋白影响的意义和机制 COUP 家族成员的转录调控活性。向着前进为了实现这一目标，本提案的目标是： (1) 确定 CTIPs在转录抑制中作用的机制基础由 COUP 家族成员介导，以及 (2) 确定生物学 CTIP 蛋白的功能。这些目标将在四个具体目标的背景：（1）阐明分子基础 ARP1.CTIP1介导的转录抑制，（2）识别靶基因受 CTIP 蛋白调节，(3) 阐明 CTIPs 在发育中的小鼠胚胎和成年大脑，（4）确定小鼠 CTIP 本申请中提出的研究将产生重大的、积极的影响对人类健康的影响有两个层面。首先，这项工作将扩大我们的了解 COUP 蛋白介导的转录抑制，可能是核受体超家族的其他成员，并且越来越多许多其他转录因子通过抑制转录健康和疾病中不依赖组蛋白脱乙酰酶的途径。其次，这个工作将为理解分子、细胞和 CTIP 蛋白的有机功能，一类新型转录蛋白抑制因子似乎在细胞调节中发挥着关键作用特定造血细胞谱系的增殖。