PMID- 10611322
OWN - NLM
STAT- MEDLINE
DCOM- 20000127
LR  - 20211203
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 26
DP  - 1999 Dec 21
TI  - Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response
      to DNA damage.
PG  - 14973-7
AB  - The p53 tumor-suppressor protein, a key regulator of cellular responses to
      genotoxic stress, is stabilized and activated after DNA damage. This process is
      associated with posttranslational modifications of p53, some of which are
      mediated by the ATM protein kinase. However, these modifications alone may not
      account in full for p53 stabilization. p53's stability and activity are
      negatively regulated by the oncoprotein MDM2, whose gene is activated by p53.
      Conceivably, p53 function may be modulated by modifications of MDM2 as well. We
      show here that after treatment of cells with ionizing radiation or a radiomimetic
      chemical, but not UV radiation, MDM2 is phosphorylated rapidly in an
      ATM-dependent manner. This phosphorylation is independent of p53 and the
      DNA-dependent protein kinase. Furthermore, MDM2 is directly phosphorylated by ATM
      in vitro. These findings suggest that in response to DNA strand breaks, ATM may
      promote p53 activity and stability by mediating simultaneous phosphorylation of
      both partners of the p53-MDM2 autoregulatory feedback loop.
FAU - Khosravi, R
AU  - Khosravi R
AD  - Department of Human Genetics, Sackler School of Medicine, Tel Aviv University,
      Ramat Aviv 69978, Israel.
FAU - Maya, R
AU  - Maya R
FAU - Gottlieb, T
AU  - Gottlieb T
FAU - Oren, M
AU  - Oren M
FAU - Shiloh, Y
AU  - Shiloh Y
FAU - Shkedy, D
AU  - Shkedy D
LA  - eng
GR  - R01 CA040099/CA/NCI NIH HHS/United States
GR  - R01 NS031763/NS/NINDS NIH HHS/United States
GR  - R01 CA40099/CA/NCI NIH HHS/United States
GR  - R011 NS31763/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.3.2.27 (MDM2 protein, human)
RN  - EC 2.3.2.27 (Mdm2 protein, mouse)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
RN  - EC 2.7.11.1 (ATM protein, human)
RN  - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
RN  - EC 2.7.11.1 (Atm protein, mouse)
RN  - EC 2.7.11.1 (DNA-Activated Protein Kinase)
RN  - EC 2.7.11.1 (PRKDC protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.1.3.1 (Alkaline Phosphatase)
SB  - IM
MH  - Alkaline Phosphatase/metabolism
MH  - Animals
MH  - Apoptosis
MH  - Ataxia Telangiectasia Mutated Proteins
MH  - Cell Cycle
MH  - Cell Cycle Proteins
MH  - DNA Damage/*physiology
MH  - DNA Repair
MH  - DNA-Activated Protein Kinase
MH  - *DNA-Binding Proteins
MH  - Feedback
MH  - Humans
MH  - Mice
MH  - *Nuclear Proteins
MH  - Phosphorylation
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-mdm2
MH  - Radiation, Ionizing
MH  - Tumor Suppressor Protein p53/*metabolism
MH  - Tumor Suppressor Proteins
PMC - PMC24757
EDAT- 1999/12/28 00:00
MHDA- 1999/12/28 00:01
CRDT- 1999/12/28 00:00
PHST- 1999/12/28 00:00 [pubmed]
PHST- 1999/12/28 00:01 [medline]
PHST- 1999/12/28 00:00 [entrez]
AID - 10.1073/pnas.96.26.14973 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14973-7. doi:
      10.1073/pnas.96.26.14973.