p300-mediated acetylation of the Notch effector transcription factor Maml-1 recruits NACK to initiate Notch-dependent transcription

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) is a critical co-activator of Notch signaling and binds to the Notch1 ternary complex. Herein we report that p300 and CBP acetylate mastermind-like transcriptional coactivator 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 was recruited to the ternary complexes containing Maml1 and Maml3, but not Maml2. Simultaneous inhibition of p300/CBP and Notch had a synergistic effect in esophageal adenocarcinoma. These results support the hypothesis that Notch transcriptional co-factors have selectivity for a specific Notch ternary complex, and they provide rationale and proof of concept for a combinatorial therapeutic attack on Notch-dependent cancers.

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