title: Acetylation of adenovirus E1A regulates binding of the transcriptional corepressor CtBP.
abstract: Adenovirus E1A mediates its effects on cellular transformation and transcription by interacting with critical cellular proteins involved in cell growth and differentiation. The amino terminus of E1A binds to CBP/p300 and associated histone acetyltransferases such as P/CAF. The carboxyl terminus binds to the carboxyl-terminal binding protein (CtBP), which associates with histone deacetylases. We show that 12S E1A can be acetylated by p300 and P/CAF and map one of the acetylation sites to Lys-239. This Lys residue is adjacent to the consensus CtBP binding motif, PXDLS. Mutation of Lys-239 to Gln or Ala blocks CtBP binding in vitro and disrupts the E1A-CtBP interaction in vivo. Peptide competition assays demonstrated that the interaction of E1A with CtBP is also blocked by Lys-239 acetylation. Supporting a functional role for Lys-239 in CtBP binding, mutation of this residue to Ala decreases the ability of E1A to block cAMP-regulated enhancer (CRE)-binding protein (CREB)-stimulated gene expression. Finally, we demonstrate that Lys-239 is acetylated in cells by using an antibody directed against an acetyl-Lys-239 E1A peptide. CtBP interacts with a wide variety of other transcriptional repressors through the PXDLS motif, and, in many instances, this motif is followed by a Lys residue. We suggest that acetylation of this residue by histone acetyltransferases, and the consequent disruption of repressor complexes, might be a general mechanism for gene activation.
authors: Vollum Institute, Oregon Health Sciences University, Portland, OR 97201, USA.
authors: Q
authors: Q
authors: Zhang
authors: H
authors: H
authors: Yao
authors: N
authors: N
authors: Vo
authors: R H
authors: RH
authors: Goodman
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D000429:Alcohol Oxidoreductases; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008239:Lysine / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D011817:Rabbits; D012097:Repressor Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
chemical_list: D000123:Acetyltransferases; D017500:Adenovirus E1A Proteins; D000429:Alcohol Oxidoreductases; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D008156:Luciferases; D008239:Lysine; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C096794:C-terminal binding protein; C494363:CREBBP protein, human