MOLECULAR ANALYSIS OF TRANSCRIPTIONAL REPRESSION BY TGIF

描述（改编自研究者摘要）：TGIF（TG相互作用 因子）是同源结构域蛋白质的TALE家族的成员。故事 同源结构域蛋白质在螺旋1之间具有三个氨基酸插入， 两个同源结构域，指定与其他DNA结合的相互作用 proteins.在人类中，TGIF突变导致前脑无裂畸形，这是一种遗传性疾病。 对颅面发育产生深远影响的紊乱。TGIF是一个 转录抑制因子，部分通过募集组蛋白 是TGF-β激活的转录共阻遏物， 斯麦兹作为对TGF-β的响应，激活的Smad复合物进入细胞核， 与DNA结合并与转录激活因子或 辅阻遏物复合物。TGIF似乎在不同的 转录调控途径：抑制 TGF-β通过Smads激活基因，并抑制第二组基因， 直接与DNA结合。然而，靶基因，由直接结合的调控， TGIF未知。本项目的目标是了解 TGIF的作用及其在转录调控中的作用。具体来说，这 该项目将在分子水平上分析TGIF的转录抑制， 并确定其在TGF-β激活的转录中的作用。靶基因 对于TGIF，和DNA结合蛋白，与TGIF相互作用，将是 鉴定这些研究将帮助我们了解TGIF的缺陷如何导致 前脑无裂畸形，并揭示了TGF-β激活的转录 调节，当受到影响Smad蛋白的突变干扰时， 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.