The ataxia-telangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53.
Levels of the tumour suppressor protein p53 are increased in response to a variety of DNA damaging agents. DNA damage-induced phosphorylation of p53 occurs at serine-15 in vivo. Phosphorylation of p53 at serine-15 leads to a stabilization of the polypeptide by inhibiting its interaction with Mdm2, a protein that targets ... p53 for ubiquitin-dependent degradation. However, the mechanisms by which DNA damage is signalled to p53 remain unclear. Here, we report the identification of a novel DNA-activated protein kinase that phosphorylates p53 on serine-15. Fractionation of HeLa nuclear extracts and biochemical analyses indicate that this kinase is distinct from the DNA-dependent protein kinase (DNA-PK) and corresponds to the human cell cycle checkpoint protein ATR. Immunoprecipitation studies of recombinant ATR reveal that catalytic activity of this polypeptide is required for DNA-stimulated phosphorylation of p53 on serine-15. These data suggest that ATR may function upstream of p53 in a signal transduction cascade initiated upon DNA damage and provide a biochemical assay system for ATR activity.
Mesh Terms:
Ataxia Telangiectasia, Catalysis, Cell Cycle Proteins, DNA, DNA-Activated Protein Kinase, DNA-Binding Proteins, HeLa Cells, Humans, Nuclear Proteins, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein-Serine-Threonine Kinases, Proteins, Serine, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, p21-Activated Kinases
Ataxia Telangiectasia, Catalysis, Cell Cycle Proteins, DNA, DNA-Activated Protein Kinase, DNA-Binding Proteins, HeLa Cells, Humans, Nuclear Proteins, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein-Serine-Threonine Kinases, Proteins, Serine, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, p21-Activated Kinases
Oncogene
Date: Jul. 08, 1999
PubMed ID: 10435622
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