MOLECULAR ANALYSIS OF TRANSCRIPTIONAL REPRESSION BY TGIF

描述(改编自调查人员摘要)：TGIF(TG-交互 因子)是同源结构域蛋白家族的一员。故事 同源结构域蛋白在螺旋1和螺旋1之间插入三个氨基酸 两个同源结构域，指定与其他DNA结合的相互作用 蛋白质。在人类中，TGIF的突变会导致全前脑畸形，这是一种基因 导致严重影响头面部发育的疾病。TGIF是一种 转录抑制因子，其部分作用是通过募集组蛋白 脱乙酰酶，是转化生长因子-β激活的转录共抑制因子 斯马德。作为对转化生长因子-β的反应，激活的Smad复合体进入细胞核， 与DNA结合，并与转录激活剂或 通过TGIF的辅助抑制物复合体。TGIF似乎在不同的地方起作用 转录调控途径：抑制转录 转化生长因子-β通过Smads激活基因并在以下情况下抑制第二组基因 直接与DNA结合。然而，靶基因，由直接结合的 TGIF是未知的。本项目的目的是为了了解 TGIF的作用及其在转录调控中的作用具体地说，这 Project将在分子水平上分析TGIF对转录的抑制， 并确定其在转化生长因子-β激活转录中的作用。靶基因 对于TGIF，以及与TGIF相互作用的DNA结合蛋白将是 已确认身份。这些研究将帮助我们理解TGIF中的缺陷是如何导致 全前脑畸形，并揭示了转化生长因子-β激活的转录 当受到影响Smad蛋白质的突变干扰时， 会导致癌症。

DESCRIPTION (Adapted from the Investigator's Abstract): TGIF (TG-interacting factor) is a member of the TALE family of homeodomain proteins. TALE homeodomain proteins have a three amino acid insertion between helices one and two of the homeodomain, which specifies interactions with other DNA binding proteins. In humans, mutation of TGIF leads to holoprosencephaly, a genetic disorder resulting in profound effects on craniofacial development. TGIF is a transcriptional repressor, which acts in part by recruiting histone deacetylases, and is a transcriptional co-repressor for TGF-beta-activated Smads. In response to TGF-beta, an activated Smad complex enters the nucleus, binds to DNA and interacts either with transcriptional activators, or a co-repressor complex via TGIF. It appears that TGIF acts in distinct transcriptional regulatory pathways: Repressing transcription of TGF-beta-activated genes via Smads and repressing a second set of genes when bound directly to DNA. However, target genes, regulated by direct binding of TGIF are not known. The goal of this project is to understand the mechanism of action of TGIF and its role in transcriptional regulation. Specifically, this project will analyze transcriptional repression by TGIF at the molecular level, and determine and its role in TGF-beta-activated transcription. Target genes for TGIF, and DNA binding proteins, with which TGIF interacts, will be identified. These studies will help us understand how defects in TGIF lead to holoprosencephaly, and shed light on TGF-beta-activated transcriptional regulation, which when perturbed by mutations affecting Smad proteins, contributes to cancer.