Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
Biochem Biophys Res Commun. 2011 Dec 16;416(3-4):300-6. doi: 10.1016/j.bbrc.2011.11.030. Epub 2011 Nov 12.
Earlier studies demonstrated the involvement of the p300 histone acetyltransferase in Notch signaling but the precise mechanisms by which p300 might modulate Notch function remains to be investigated. In this study, we show that p300 acetylates Notch1 ICD in cell culture assay and in vitro, and conserved lysines located within the Notch C-terminal nuclear localization signal are essential for Notch acetylation. MAML1 and CSL, which are components of the Notch transcription complex, enhance Notch acetylation and we suggest that MAML1 increases Notch acetylation by potentiating p300 autoacetylation. Furthermore, MAML1-dependent acetylation of Notch1 ICD by p300 decreases the ubiquitination of Notch1 ICD in cellular assays. CDK8 has been shown to target Notch1 for ubiquitination and proteosomal degradation. We show that CDK8 inhibits Notch acetylation and Notch transcription enhanced by p300. Therefore, we speculate that acetylation of Notch1 might be a mechanism to regulate Notch activity by interfering with ubiquitin-dependent pathways.
早期研究表明 p300 组蛋白乙酰转移酶参与了 Notch 信号通路，但 p300 调节 Notch 功能的具体机制仍有待研究。在这项研究中，我们发现在细胞培养实验和体外实验中 p300 使 Notch1 ICD 乙酰化，并且位于 Notch 羧基端核定位信号内的保守赖氨酸对于 Notch 乙酰化是必需的。MAML1 和 CSL 是 Notch 转录复合物的组成部分，它们增强了 Notch 的乙酰化，我们推测 MAML1 通过增强 p300 自乙酰化来增加 Notch 的乙酰化。此外，MAML1 依赖性 p300 对 Notch1 ICD 的乙酰化在细胞实验中降低了 Notch1 ICD 的泛素化。CDK8 已被证明可靶向 Notch1 进行泛素化和蛋白酶体降解。我们发现 CDK8 抑制由 p300 增强的 Notch 乙酰化和转录。因此，我们推测 Notch1 的乙酰化可能是通过干扰泛素依赖途径来调节 Notch 活性的一种机制。
