The Genomic Response of Tumor Cells to Hypoxia and Reoxygenation

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Abstract
Hypoxia and reoxygenation are important pathophysiological conditions that occur during injury, ischemia, reperfusion and stroke. In tumors, hypoxia and oxidative stress are regarded as triggers for enhanced proliferation and metastasis. Hypoxia and reoxygenation exert part of their biological effects by inducing the expression of novel genes but very little is known about the transcription factors involved. Here, we have compared the behaviour of two redox-controlled factors, AP-1 and NF-κB, during hypoxia and reoxygenation. We report that the DNA-binding and transcriptional activity of transcription factor AP-1 is very strongly induced in a biphasic response when HeLa cells are exposed to reduced oxygen pressure. This induction required new AP-1 protein synthesis. Different members of the Jun/Fos family of transcription factors were found in the first and second maxima of activation. The pathogen-responsive, pre-existing transcription factor NF-κB was not activated under hypoxic conditions. However, a p50-p65 heterodimer of NF-κB was rapidly and strongly activated when HeLa cells were re-exposed to normal oxygen pressure. This explains the induction of NF-κB-controlled inflammatory cytokine genes during reperfusion of ischemic tissue. Our data suggest that the genomic response to hypoxia is primarily mediated by AP-1 while the inflammatory response to reoxygenation is mediated by NF-κB.