Acetyltransferases in Transformation by c-MYC

描述（由申请人提供）：我们分离了一种新的转录本， 辅因子，其募集对于c-MYC的转化至关重要 癌蛋白TRRAP蛋白是几种组蛋白的组成部分， 通过染色质调节转录的乙酰转移酶复合物 改性我们还首次表明，c-MYC本身被修饰， 体外和体内乙酰化。此外，两类TRRAP相关的 乙酰转移酶能够在体内乙酰化c-MYC。 指导假设和具体目标：我们假设TRRAP辅因子 复合物对于c-MYC的细胞转化至关重要， 它们调节下游靶基因子集的表达。的 我们的主要目标是鉴定这一基因子集。一旦确定，我们 将确定这些基因参与c-MYC的机制 生物功能。此外，我们还将对 c-MYC/TRRAP相互作用。这将包括在434 kDa上定义域 TRRAP蛋白与c-MYC结合并决定TRRAP在组装中的作用 和乙酰转移酶复合物本身的功能。 创新和意义：TRRAP辅因子的鉴定和 证明它是由c-MYC招募是新的观察，形成 这一提议的基础。因为这次招募对于 我们将在c-MYC中使用特定的突变体，这些突变体在转化中是有缺陷的。 TRRAP招募以探测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.