Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
Cancer Res. 2017 Aug 15;77(16):4228-4237. doi: 10.1158/0008-5472.CAN-16-3156. Epub 2017 Jun 16.
Although it has long been appreciated that p300 acts as a critical Notch coactivator, the mechanistic details of p300 in Notch-mediated transcription remain unclear. We previously demonstrated that PEAK1-related kinase activating pseudokinase 1 (NACK), also known as SGK223, is a critical coactivator of Notch signaling and binds to the Notch1 ternary complex. Herein we report that p300 and CBP acetylate Mastermind-like 1 (Maml1) on amino acid residues K188 and K189 to recruit NACK to the Notch1 ternary complex, which results in the recruitment of RNA polymerase II to initiate transcription. NACK is recruited to the ternary complexes containing Maml1 and Maml3, but not Maml2. Simultaneous inhibition of p300/CBP and Notch has a synergistic effect in esophageal adenocarcinoma. In summary, this study provides a deeper mechanistic understanding of the assembly of the Notch transcriptional complex and provides rationale and proof of concept for a combinatorial therapeutic attack on Notch-dependent cancers. .
虽然人们早就认识到 p300 是 Notch 的关键共激活因子，但 p300 在 Notch 介导的转录中的作用机制仍不清楚。我们之前的研究表明，PEAK1 相关激酶激活拟激酶 1（NACK），也称为 SGK223，是 Notch 信号的关键共激活因子，与 Notch1 三元复合物结合。在此，我们报告 p300 和 CBP 乙酰化 Mastermind-like 1（Maml1）上的氨基酸残基 K188 和 K189，以招募 NACK 到 Notch1 三元复合物，从而招募 RNA 聚合酶 II 启动转录。NACK 被招募到含有 Maml1 和 Maml3 的三元复合物中，但不被招募到含有 Maml2 的三元复合物中。同时抑制 p300/CBP 和 Notch 在食管腺癌中具有协同作用。总之，这项研究为 Notch 转录复合物的组装提供了更深入的机制理解，并为针对 Notch 依赖性癌症的联合治疗提供了依据和概念验证。
