Cell type and promoter-specific roles of Ser18 phosphorylation in regulating p53 responses

C Chao, M Hergenhahn, M. D Kaeser, Z Wu, S Saito, Richard Derek Iggo, M Hollstein, E Apella, Y Xu

Research output: Contribution to journalArticlepeer-review

118 Citations (Scopus)

Abstract

Phosphorylation of mouse p53 at Ser(18) occurs after DNA damage. To determine the physiological roles of this phosphorylation event in p53-dependent DNA damage responses, a Ser(18) 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 Ser(18) 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 Ser(18) by ATM nor a full transcriptional response is essential to prevent spontaneous tumor formation in mice.

Original languageEnglish
Pages (from-to)41028-41033
Number of pages6
JournalJournal of Biological Chemistry
Volume278
DOIs
Publication statusPublished - 17 Oct 2003

Keywords

  • DAMAGE-INDUCED PHOSPHORYLATION
  • DNA-DAMAGE
  • IN-VIVO
  • APOPTOSIS
  • MDM2
  • RECRUITMENT
  • DEGRADATION
  • EXPRESSION
  • SERINE-15
  • PATHWAYS

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