Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1128/MCB.26.5.1598-1609.2006

Type

Journal article

Journal

Mol Cell Biol

Publication Date

03/2006

Volume

26

Pages

1598 - 1609

Keywords

Acetylcysteine, Apoptosis, Ataxia Telangiectasia, Carcinoma, Cell Hypoxia, Cell Survival, Checkpoint Kinase 2, Colorectal Neoplasms, DNA Damage, Free Radical Scavengers, G2 Phase, Humans, Oxygen, Phosphorylation, Protein-Serine-Threonine Kinases, Reactive Oxygen Species, Threonine, Tumor Cells, Cultured, Tumor Suppressor Protein p53, cdc25 Phosphatases