Transcriptional Repression Mechanisms of COUP Proteins

描述：（从申请人摘要中扫描）COUP家族成员 孤儿核受体（COUP-TFI，ARP 1和Ear 2）发挥关键作用，但效果不佳 了解胎儿发育中的作用，包括神经发生和血管生成， 以及成年生物体内稳态调节机制。这些蛋白质 通常认为在组蛋白中起转录抑制因子的作用 脱乙酰酶依赖性途径。我们最近发现了一种机械地 COUP介导的转录抑制的新途径，不涉及 抑制素A敏感性组蛋白脱乙酰酶的作用。一个关键组成部分 在这条途径中，两种新的组织特异性表达的 CTIP 1和CTIP 2蛋白，两者都是C2 H2锌指蛋白， 与所有COUP家族成员直接相互作用并募集孤儿受体 与转录沉默相关的异染色质基因座。CTIP 也是抑制CTIP应答转录的DNA结合蛋白 在哺乳动物细胞中的元件独立于COUP蛋白。CTIP 蛋白质具有巨大的生物医学意义，这不仅是因为它们在生物医学中的作用， 新的COUP信号传导机制，作为真正的转录因子，因为 小鼠CTIP 1基因座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的发生 这个实验室的长期目标是阐明 CTIP蛋白影响细胞凋亡的意义和机制 COUP家族成员的转录调节活性。进军 这一目标，这一建议的目标是：（1）确定 CTIP在转录抑制中作用的机制基础 由COUP家族成员介导，和（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）鉴定靶基因 （3）阐明CTIPs的表达模式， 发育中的小鼠胚胎和成年大脑;（4）确定 小鼠中的CTIP 本申请中提出的研究将具有重大的、积极的意义。 对人体健康的影响有两个层面。首先，这项工作将扩大我们的 理解COUP蛋白介导的转录抑制， 可能是核受体超家族的其他成员， 抑制转录的其他转录因子的数量， 健康和疾病中组蛋白脱乙酰酶独立途径。其次 这项工作将为理解分子、细胞和 CTIP蛋白的生物功能，一类新的转录 阻遏物似乎在调节细胞凋亡中起着关键作用， 在特定的造血细胞谱系中增殖。

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.