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PMID: 16478982 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

DNA damage during reoxygenation elicits a Chk2-dependent checkpoint response.

Molecular and cellular biology ·Vol. 26 ·No. 5 ·2006-03-00 ·Pages 1598-609

Freiberg RA, Hammond EM, Dorie MJ, Welford SM, Giaccia AJ

Abstract

Due to the abnormal vasculature of solid tumors, tumor cell oxygenation can change rapidly with the opening and closing of blood vessels, leading to the activation of both hypoxic response pathways and oxidative stress pathways upon reoxygenation. Here, we report that ataxia telangiectasia mutated-dependent phosphorylation and activation of Chk2 occur in the absence of DNA damage during hypoxia and are maintained during reoxygenation in response to DNA damage. Our studies involving oxidative damage show that Chk2 is required for G2 arrest. Following exposure to both hypoxia and reoxygenation, Chk2-/- cells exhibit an attenuated G2 arrest, increased apoptosis, reduced clonogenic survival, and deficient phosphorylation of downstream targets. These studies indicate that the combination of hypoxia and reoxygenation results in a G2 checkpoint response that is dependent on the tumor suppressor Chk2 and that this checkpoint response is essential for tumor cell adaptation to changes that result from the cycling nature of hypoxia and reoxygenation found in solid tumors.

MeSH Terms
Acetylcysteine/pharmacology Apoptosis/physiology Ataxia Telangiectasia/metabolism,pathology Carcinoma/drug therapy,metabolism,pathology Cell Hypoxia Cell Survival Checkpoint Kinase 2 Colorectal Neoplasms/drug therapy,metabolism,pathology DNA Damage/drug effects,physiology Free Radical Scavengers/pharmacology G2 Phase/physiology Humans Oxygen/metabolism Phosphorylation Protein Serine-Threonine Kinases/genetics,metabolism Reactive Oxygen Species/metabolism Threonine/metabolism Tumor Cells, Cultured Tumor Suppressor Protein p53/genetics,metabolism cdc25 Phosphatases/metabolism
Chemicals
Free Radical Scavengers Reactive Oxygen Species Tumor Suppressor Protein p53 Threonine Checkpoint Kinase 2 CHEK2 protein, human Protein Serine-Threonine Kinases CDC25A protein, human cdc25 Phosphatases Oxygen Acetylcysteine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Freiberg Rachel A
CCSR South, Room 1255, Department of Radiation Oncology, Stanford University, Stanford, CA 94305-5152, USA.
Hammond Ester M
Dorie Mary Jo
Welford Scott M
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.26.5.1598-1609.2006
Published
2006-03-00
Pages
1598-609
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1430245
Subset
IM
Grants
NCI NIH HHS · R01 CA088480 · United States
NCI NIH HHS · R37 CA088480 · United States
NCI NIH HHS · T32 CA009151 · United States
NCI NIH HHS · CA 88480 · United States
External Links
PubMed source DOI: 10.1128/MCB.26.5.1598-1609.2006 PMC Full Text View journal details
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