PMID- 10570149
OWN - NLM
STAT- MEDLINE
DCOM- 20000106
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 24
DP  - 1999 Nov 23
TI  - Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA 
      damage.
PG  - 13777-82
AB  - Stabilization of p53 in response to DNA damage is caused by its dissociation from
      Mdm2, a protein that targets p53 for degradation in the proteasome. Dissociation 
      of p53 from Mdm2 could be caused by DNA damage-induced p53 posttranslational
      modifications. The ATM and ATR kinases, whose activation in response to ionizing 
      radiation (IR) and UV light, respectively, is required for p53 stabilization,
      directly phosphorylate p53 on Ser-15. However, phosphorylation of Ser-15 is
      critical for the apoptotic activity of p53 and not for p53 stabilization. Thus,
      whether any p53 modifications, and which, underlie disruption of the p53-Mdm2
      complex after DNA damage remains to be determined. We analyzed the IR- and UV
      light-induced stabilization of p53 proteins with substitutions of Ser known to be
      posttranslationally modified after DNA damage. Substitution of Ser-20 was
      sufficient to abrogate p53 stabilization in response to both IR and UV light.
      Furthermore, both IR and UV light induced phosphorylation of p53 on Ser-20, which
      involved the majority of nuclear p53 protein and weakened the interaction of p53 
      with Mdm2 in vitro. ATM and ATR cannot phosphorylate p53 on Ser-20. We therefore 
      propose that ATM and ATR activate an, as yet unidentified, kinase that stabilizes
      p53 by phosphorylating it on Ser-20.
FAU - Chehab, N H
AU  - Chehab NH
AD  - Department of Molecular Genetics, The Wistar Institute, Philadelphia, PA 19104,
      USA.
FAU - Malikzay, A
AU  - Malikzay A
FAU - Stavridi, E S
AU  - Stavridi ES
FAU - Halazonetis, T D
AU  - Halazonetis TD
LA  - eng
GR  - R01 CA076367/CA/NCI NIH HHS/United States
GR  - T32 CA009171/CA/NCI NIH HHS/United States
GR  - CA76367/CA/NCI NIH HHS/United States
GR  - T32 CA09171/CA/NCI 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 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 452VLY9402 (Serine)
RN  - EC 2.3.2.27 (MDM2 protein, human)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
SB  - IM
MH  - Binding Sites
MH  - *DNA Damage/radiation effects
MH  - Humans
MH  - Mutagenesis, Site-Directed
MH  - *Nuclear Proteins
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins/chemistry/metabolism
MH  - Proto-Oncogene Proteins c-mdm2
MH  - Serine/genetics/*metabolism
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Protein p53/chemistry/genetics/*metabolism
PMC - PMC24141
EDAT- 1999/11/26 00:00
MHDA- 1999/11/26 00:01
CRDT- 1999/11/26 00:00
PHST- 1999/11/26 00:00 [pubmed]
PHST- 1999/11/26 00:01 [medline]
PHST- 1999/11/26 00:00 [entrez]
AID - 10.1073/pnas.96.24.13777 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13777-82. doi:
      10.1073/pnas.96.24.13777.