PDF(Pubmed)
Abstract：
The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and the functions of specific acetylated lysine (AcK) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various malignant and nonmalignant cells. Oncogenic overexpression of MYC enhances its acetylation and alters the regulation of site-specific acetylation by proteasome and deacetylase inhibitors. Acetylation of MYC at different K residues differentially affects its stability in a cell type-dependent manner. Lysine-to-arginine substitutions indicate that although none of the AcK residues is required for MYC stimulation of adherent cell proliferation, individual AcK sites have gene-specific functions controlling select MYC-regulated processes in cell adhesion, contact inhibition, apoptosis, and/or metabolism and are required for the malignant cell transformation activity of MYC. Each AcK site is required for anchorage-independent growth of MYC-overexpressing cells in vitro, and both the AcK148(149) and AcK157(158) residues are also important for the tumorigenic activity of MYC transformed cells in vivo. The MYC AcK site-specific signaling pathways identified may offer new avenues for selective therapeutic targeting of MYC oncogenic activities.
摘要：
MYC致癌转录因子被p300和GCN5组蛋白乙酰转移酶乙酰化。MYC乙酰化的意义和特定乙酰化赖氨酸（AcK）残基的功能仍不清楚。这里,我们显示，人（或小鼠）MYC中主要的p300-乙酰化K148（149）和K157（158）位点以及主要的GCN5-乙酰化K323残基在各种恶性和非恶性细胞中可逆地乙酰化。MYC的致癌过表达增强其乙酰化并改变蛋白酶体和脱乙酰酶抑制剂对位点特异性乙酰化的调节。MYC在不同K残基的乙酰化以细胞类型依赖性方式差异影响其稳定性。赖氨酸到精氨酸的取代表明，尽管MYC刺激贴壁细胞增殖不需要AcK残基，单个AcK位点具有基因特异性功能，控制细胞粘附中选择MYC调节的过程，接触抑制,凋亡，和/或代谢，并且是MYC的恶性细胞转化活性所必需的。每个AcK位点对于体外MYC过表达细胞的锚定非依赖性生长是必需的，AcK148(149)和AcK157(158)残基对于体内MYC转化细胞的致瘤活性也是重要的。鉴定的MYCAcK位点特异性信号通路可能为MYC致癌活性的选择性治疗靶向提供新的途径。
