PMID- 10435622
OWN - NLM
STAT- MEDLINE
DCOM- 19990817
LR  - 20131121
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 18
IP  - 27
DP  - 1999 Jul 8
TI  - The ataxia-telangiectasia related protein ATR mediates DNA-dependent
      phosphorylation of p53.
PG  - 3989-95
AB  - 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.
FAU - Lakin, N D
AU  - Lakin ND
AD  - Wellcome Trust/Cancer Research Campaign Institute of Cancer and Developmental
      Biology, Department of Zoology, Cambridge University, UK.
FAU - Hann, B C
AU  - Hann BC
FAU - Jackson, S P
AU  - Jackson SP
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proteins)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 452VLY9402 (Serine)
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (ATM protein, human)
RN  - EC 2.7.11.1 (ATR protein, human)
RN  - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
RN  - EC 2.7.11.1 (DNA-Activated Protein Kinase)
RN  - EC 2.7.11.1 (PAK1 protein, human)
RN  - EC 2.7.11.1 (PRKDC protein, human)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (p21-Activated Kinases)
SB  - IM
MH  - Ataxia Telangiectasia/enzymology/*metabolism
MH  - Ataxia Telangiectasia Mutated Proteins
MH  - Catalysis
MH  - Cell Cycle Proteins/*physiology
MH  - DNA/physiology
MH  - DNA-Activated Protein Kinase
MH  - *DNA-Binding Proteins
MH  - HeLa Cells
MH  - Humans
MH  - Nuclear Proteins
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Protein-Serine-Threonine Kinases/metabolism
MH  - Proteins/*physiology
MH  - Serine/metabolism
MH  - Tumor Suppressor Protein p53/metabolism
MH  - Tumor Suppressor Proteins
MH  - p21-Activated Kinases
EDAT- 1999/08/06 00:00
MHDA- 1999/08/06 00:01
CRDT- 1999/08/06 00:00
PHST- 1999/08/06 00:00 [pubmed]
PHST- 1999/08/06 00:01 [medline]
PHST- 1999/08/06 00:00 [entrez]
AID - 10.1038/sj.onc.1202973 [doi]
PST - ppublish
SO  - Oncogene. 1999 Jul 8;18(27):3989-95. doi: 10.1038/sj.onc.1202973.