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PMID: 11865061 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Hypoxia links ATR and p53 through replication arrest.

Molecular and cellular biology ·Vol. 22 ·No. 6 ·2002-03-00 ·Pages 1834-43

Hammond EM, Denko NC, Dorie MJ, Abraham RT, Giaccia AJ

Abstract

Previous studies have demonstrated that phosphorylation of human p53 on serine 15 contributes to protein stabilization after DNA damage and that this is mediated by the ATM family of kinases. However, cellular exposure to hypoxia does not induce any detectable level of DNA lesions compared to ionizing radiation, and the oxygen dependency of p53 protein accumulation differs from that of HIF-1, the hypoxia-inducible transcription factor. Here we show that, under severe hypoxic conditions, p53 protein accumulates only in S phase and this accumulation correlates with replication arrest. Inhibition of ATR kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation. Thus, hypoxia-induced cell growth arrest is tightly linked to an ATR-signaling pathway that is required for p53 modification and accumulation. These studies indicate that the ATR kinase plays an important role during tumor development in responding to hypoxia-induced replication arrest, and hypoxic conditions could select for the loss of key components of ATR-dependent checkpoint controls.

MeSH Terms
Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins Cell Division/physiology Cell Hypoxia/physiology Cell Line Cell Nucleus/metabolism Cobalt/pharmacology Comet Assay DNA Damage/drug effects DNA Replication/drug effects Enzyme Inhibitors/pharmacology Humans Hypoxia-Inducible Factor 1, alpha Subunit Iron Chelating Agents/pharmacology Oligonucleotide Array Sequence Analysis Phosphorylation/drug effects Protein Serine-Threonine Kinases/antagonists & inhibitors,metabolism S Phase/physiology Signal Transduction/physiology Stress, Physiological/metabolism Transcription Factors/metabolism Tumor Suppressor Protein p53/metabolism
Chemicals
Cell Cycle Proteins Enzyme Inhibitors HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit Iron Chelating Agents Transcription Factors Tumor Suppressor Protein p53 Cobalt ATR protein, human Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases cobaltous chloride
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Hammond Ester M
Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA 94303-5152, USA.
Denko Nicholas C
Dorie Mary Jo
Abraham Robert T
Giaccia Amato J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.22.6.1834-1843.2002
Published
2002-03-00
Pages
1834-43
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC135616
Subset
IM
Grants
NCI NIH HHS · P01 CA067166 · United States
NCI NIH HHS · CA 67166 · United States
NCI NIH HHS · CA 88480 · United States
NCI NIH HHS · R01 CA088480 · United States
NCI NIH HHS · R37 CA088480 · United States
External Links
PubMed source DOI: 10.1128/MCB.22.6.1834-1843.2002 PMC Full Text View journal details
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