title: Ubiquitination of Notch1 is regulated by MAML1-mediated p300 acetylation of Notch1.
abstract: 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.
authors.affiliation: Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Anita E
authors.initials: AE
authors.lastname: Popko-Scibor
authors.forename: Mikael J
authors.initials: MJ
authors.lastname: Lindberg
authors.forename: Magnus L
authors.initials: ML
authors.lastname: Hansson
authors.forename: Teresa
authors.initials: T
authors.lastname: Holmlund
authors.forename: Annika E
authors.initials: AE
authors.lastname: Wallberg
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D054875:Ubiquitination; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D056850:Cyclin-Dependent Kinase 8; D004268:DNA-Binding Proteins; D008239:Lysine; D051881:Receptor, Notch1; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C430872:MAML1 protein, human; C497762:Notch1 protein, mouse; C095686:CDK8 protein, human