Acetyltransferases in Transformation by c-MYC

描述(申请人提供)：我们已经分离出一种新的转录 辅因子，其招募对c-myc的转变至关重要 癌蛋白。这种名为TRRAP的蛋白质是几种组蛋白的组成部分 通过染色质调节转录的乙酰基转移酶复合体 修改。我们还首次证明了c-myc本身是由 体外和体内的乙酰化。此外，这两类与TRRAP相关的 乙酰转移酶在体内具有乙酰化c-myc的功能。 指导性假设和具体目标：我们假设TRRAP的辅助因素 复合体对c-myc的细胞转化至关重要，因为 它们调节下游靶基因的子集的表达。这个 识别这个基因的子集是我们的主要目标。一旦确定，我们 将定义这些基因参与c-myc的机制。S 生物功能。此外，我们还将对 C-MYC/TRRAP相互作用。这将包括定义434 kDa上的域 与c-myc结合的TRRAP蛋白及其在组装中的作用 和乙酰基转移酶复合体本身的功能。 创新和意义：TRRAP辅因子的确定和 证明它是由c-myc招募的是新的观察结果，形成 这项建议的基础。因为这次招聘似乎对 转化，我们将使用c-myc中的特定突变体，这些突变体对 TRRAP招募以探索c-myc调控的遗传级联反应 转型。

DESCRIPTION (provided by applicant): We have isolated a novel transcriptional cofactor whose recruitment is essential for transformation by the c-MYC oncoprotein. This protein, TRRAP is a component of several histone acetyltransferase complexes that regulate transcription via chromatin modification. We also show for the first time that c-MYC itself is modified by acetylation in vitro and in vivo. Furthermore, both classes of TRRAP-associated acetyltransferase are capable of acetylating c-MYC in vivo. Guiding Hypothesis and Specific Aims: We hypothesize that the TRRAP cofactor complexes are critical for cellular transformation by c-MYC because together they regulate the expression of a subset of downstream target genes. The identification of this subset of genes is our primary goal. Once identified, we will define the mechanism by which these genes participate in c -MYC' s biological functions. In addition, we will biochemically characterized the c-MYC/TRRAP interaction. This will include defining the domain on the 434 kDa TRRAP protein bound by c-MYC and determining the role of TRRAP in the assembly and function of the acetyltransferase complexes themselves. Innovation and Significance: The identification of the TRRAP cofactor and the demonstration that it is recruited by c-MYC are novel observations that form the basis of this proposal. Because this recruitment appears critical for transformation, we will use specific mutants in c-MYC which are defective for TRRAP recruitment to probe the genetic cascade regulated by c-MYC in transformation.