Oncology Discovery, Merck & Co., Inc., Boston, MA, USA.
Biologics Process R&D, Merck & Co., Inc., Kenilworth, NJ, USA.
FEBS Lett. 2020 May;594(10):1467-1476. doi: 10.1002/1873-3468.13759. Epub 2020 Mar 11.
Myc, a transcription factor with oncogenic activity, is upregulated by amplification, translocation, and mutation of the cellular pathways that regulate its stability. Inhibition of the Myc oncogene by various modalities has had limited success. One Myc inhibitor, Omomyc, has limited cellular and in vivo activity. Here, we report a mini-protein, referred to as Mad, which is derived from the cellular Myc antagonist Mxd1. Mad localizes to the nucleus in cells and is 10-fold more potent than Omomyc in inhibiting Myc-driven cell proliferation. Similar to Mxd1, Mad also interacts with Max, the binding partner of Myc, and with the nucleolar upstream binding factor. Mad binds to E-Box DNA in the promoters of Myc target genes and represses Myc-mediated transcription to a greater extent than Omomyc. Overall, Mad appears to be more potent than Omomyc both in vitro and in cells.
Myc 是一种具有致癌活性的转录因子，其表达水平可通过调节其稳定性的细胞通路的扩增、易位和突变而上调。通过各种方式抑制 Myc 癌基因的活性取得的效果有限。一种 Myc 抑制剂 Omomyc 的细胞和体内活性有限。在这里，我们报告了一种称为 Mad 的小蛋白，它来源于细胞 Myc 拮抗剂 Mxd1。Mad 在细胞内定位于细胞核，抑制 Myc 驱动的细胞增殖的效力比 Omomyc 强 10 倍。与 Mxd1 相似，Mad 还与 Myc 的结合伙伴 Max 和核仁上游结合因子相互作用。Mad 结合到 Myc 靶基因启动子中的 E-Box DNA 上，并抑制 Myc 介导的转录，其抑制程度比 Omomyc 更强。总的来说，Mad 在体外和细胞内似乎比 Omomyc 更有效。
