Freiberg Rachel A, Hammond Ester M, Dorie Mary Jo, Welford Scott M, Giaccia Amato J
CCSR South, Room 1255, Department of Radiation Oncology, Stanford University, Stanford, CA 94305-5152, USA.
Mol Cell Biol. 2006 Mar;26(5):1598-609. doi: 10.1128/MCB.26.5.1598-1609.2006.
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.
由于实体瘤血管系统异常，肿瘤细胞的氧合作用会随着血管的开闭而迅速变化，导致在再氧合时缺氧反应途径和氧化应激途径均被激活。在此，我们报告，共济失调毛细血管扩张症突变（ATM）依赖性的Chk2磷酸化及激活在缺氧期间无DNA损伤时发生，并在再氧合期间因DNA损伤而持续存在。我们涉及氧化损伤的研究表明，G2期阻滞需要Chk2。暴露于缺氧和再氧合后，Chk2基因敲除细胞表现出减弱的G2期阻滞、凋亡增加、克隆存活减少以及下游靶点磷酸化缺陷。这些研究表明，缺氧和再氧合的联合作用导致了依赖肿瘤抑制因子Chk2的G2期检查点反应，并且这种检查点反应对于肿瘤细胞适应实体瘤中缺氧和再氧合循环性质所导致的变化至关重要。
