Abstract
Phosphorylation of mouse p53 at Ser18 occurs after DNA damage. To determine the physiological roles of this phosphorylation event in p53-dependent DNA damage responses, a Ser18 to Ala missense mutation was introduced into the germline of mice. Thymocytes and fibroblasts from the knock-in mice show reduced transactivation of many p53 target genes following DNA damage. p53 protein stabilization and DNA binding are similar in knock-in and wild type mice, but C-terminal acetylation was defective, consistent with a role for Ser18 in the recruitment of transcriptional co-activators. The apoptotic response of knock-in thymocytes to ionizing radiation is intermediate between that of wild type and p53 null thymocytes. Despite impaired transcriptional and apoptotic responses, the knock-in mice are not prone to spontaneous tumorigenesis. This indicates that neither phosphorylation of p53 on Ser18 by ATM nor a full transcriptional response is essential to prevent spontaneous tumor formation in mice.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis
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Ataxia Telangiectasia Mutated Proteins
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Blotting, Western
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Cell Cycle
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Cell Cycle Proteins
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Chromatin / metabolism
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DNA Damage
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DNA-Binding Proteins
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Dose-Response Relationship, Radiation
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Fibroblasts / metabolism
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Mice
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Mice, Transgenic
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Oligonucleotide Array Sequence Analysis
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Phosphorylation
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Precipitin Tests
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Promoter Regions, Genetic*
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Tertiary
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Serine / chemistry*
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Serine / metabolism
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Thymus Gland / cytology
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Thymus Gland / metabolism
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Time Factors
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Transcription, Genetic
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Transcriptional Activation
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins
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Ultraviolet Rays
Substances
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Cell Cycle Proteins
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Chromatin
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DNA-Binding Proteins
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RNA, Messenger
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Serine
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases