Ubiquitination of Notch1 Is Regulated by MAML1-mediated p300 Acetylation of Notch1

Biochem Biophys Res Commun. 2011 Dec 16;416(3-4):300-6. doi: 10.1016/j.bbrc.2011.11.030. Epub 2011 Nov 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Animals
  • Cyclin-Dependent Kinase 8 / metabolism
  • DNA-Binding Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Lysine / chemistry
  • Lysine / metabolism
  • Mice
  • Molecular Sequence Data
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Receptor, Notch1 / metabolism*
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Ubiquitination*
  • p300-CBP Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • MAML1 protein, human
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Transcription Factors
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • CDK8 protein, human
  • Cyclin-Dependent Kinase 8
  • Lysine