title: SIAH-mediated ubiquitination and degradation of acetyl-transferases regulate the p53 response and protein acetylation.
abstract: Posttranslational modification of proteins by lysine acetylation regulates many biological processes ranging from signal transduction to chromatin compaction. Here we identify the acetyl-transferases CBP/p300, Tip60 and PCAF as new substrates for the ubiquitin E3 ligases SIAH1 and SIAH2. While CBP/p300 can undergo ubiquitin/proteasome-dependent degradation by SIAH1 and SIAH2, the two other acetyl-transferases are exclusively degraded by SIAH2. Accordingly, SIAH-deficient cells show enhanced protein acetylation, thus revealing SIAH proteins as indirect regulators of the cellular acetylation status. Functional experiments show that Tip60/PCAF-mediated acetylation of the tumor suppressor p53 is antagonized by the p53 target gene SIAH2 which mediates ubiquitin/proteasome-mediated degradation of both acetyl-transferases and consequently diminishes p53 acetylation and transcriptional activity. The p53 kinase HIPK2 mediates hierarchical phosphorylation of SIAH2 at 5 sites, which further boosts its activity as a ubiquitin E3 ligase for several substrates and therefore dampens the late p53 response.
authors.affiliation: Department of Biochemistry, Medical Faculty, Friedrichstrasse 24, Justus Liebig University, Member of the German Center for Lung Research, 35392 Giessen, Germany.
authors.forename: Inna
authors.initials: I
authors.lastname: Grishina
authors.forename: Katherina
authors.initials: K
authors.lastname: Debus
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Limones
authors.forename: Constanze
authors.initials: C
authors.lastname: Schneider
authors.forename: Amit
authors.initials: A
authors.lastname: Shresta
authors.forename: Carlos
authors.initials: C
authors.lastname: García
authors.forename: Marco A
authors.initials: MA
authors.lastname: Calzado
authors.forename: M Lienhard
authors.initials: ML
authors.lastname: Schmitz
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D015180:Electrophoresis, Gel, Two-Dimensional; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D018345:Mice, Knockout; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000737:chemistry / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*; D054875:Ubiquitination; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D000074443:Lysine Acetyltransferase 5; D011506:Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C098489:KAT5 protein, human; C484442:Siah1a protein, mouse; C533102:Siah2 protein, mouse