Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Cell. 2010 Aug 6;142(3):480-93. doi: 10.1016/j.cell.2010.06.037.
The Myc oncoprotein family comprises transcription factors that control multiple cellular functions and are widely involved in oncogenesis. Here we report the identification of Myc-nick, a cytoplasmic form of Myc generated by calpain-dependent proteolysis at lysine 298 of full-length Myc. Myc-nick retains conserved Myc box regions but lacks nuclear localization signals and the bHLHZ domain essential for heterodimerization with Max and DNA binding. Myc-nick induces alpha-tubulin acetylation and altered cell morphology by recruiting histone acetyltransferase GCN5 to microtubules. During muscle differentiation, while the levels of full-length Myc diminish, Myc-nick and acetylated alpha-tubulin levels are increased. Ectopic expression of Myc-nick accelerates myoblast fusion, triggers the expression of myogenic markers, and permits Myc-deficient fibroblasts to transdifferentiate in response to MyoD. We propose that the cleavage of Myc by calpain abrogates the transcriptional inhibition of differentiation by full-length Myc and generates Myc-nick, a driver of cytoplasmic reorganization and differentiation.
Myc 癌基因家族由转录因子组成，这些转录因子控制多种细胞功能，广泛参与肿瘤发生。在这里，我们报告了 Myc-nick 的鉴定，Myc-nick 是全长 Myc 在赖氨酸 298 处被钙蛋白酶依赖性蛋白水解产生的细胞质形式。Myc-nick 保留了保守的 Myc 盒区域，但缺乏核定位信号和与 Max 形成异二聚体以及与 DNA 结合所必需的 bHLHZ 结构域。Myc-nick 通过将组蛋白乙酰转移酶 GCN5 招募到微管上来诱导微管相关蛋白 α-微管蛋白的乙酰化和细胞形态的改变。在肌肉分化过程中，尽管全长 Myc 的水平下降，但 Myc-nick 和乙酰化的α-微管蛋白水平增加。Myc-nick 的异位表达可加速成肌细胞融合，触发肌生成标志物的表达，并使缺乏 Myc 的成纤维细胞能够响应 MyoD 进行转分化。我们提出，钙蛋白酶对 Myc 的切割消除了全长 Myc 对分化的转录抑制，并产生了 Myc-nick，这是细胞质重排和分化的驱动因素。
