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.
Copyright © 2012 Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Acetyltransferases / genetics
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Acetyltransferases / metabolism*
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Animals
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Blotting, Western
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Cells, Cultured
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Electrophoresis, Gel, Two-Dimensional
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Fluorescent Antibody Technique
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Histone Acetyltransferases / genetics
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Histone Acetyltransferases / metabolism
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Humans
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Immunoenzyme Techniques
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Immunoprecipitation
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Lysine Acetyltransferase 5
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Mice
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Mice, Knockout
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Protein Conformation
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Protein Processing, Post-Translational*
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Proteins / chemistry
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Proteins / physiology*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Transcriptional Activation
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Ubiquitin / metabolism*
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Ubiquitin-Protein Ligases / chemistry
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Ubiquitin-Protein Ligases / physiology*
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Ubiquitination
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p300-CBP Transcription Factors / genetics
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p300-CBP Transcription Factors / metabolism
Substances
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Proteins
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RNA, Messenger
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Tumor Suppressor Protein p53
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Ubiquitin
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Acetyltransferases
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Histone Acetyltransferases
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KAT5 protein, human
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Lysine Acetyltransferase 5
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p300-CBP Transcription Factors
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p300-CBP-associated factor
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Siah1a protein, mouse
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Siah2 protein, mouse
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Ubiquitin-Protein Ligases