Modeling the regulation of p53 activation by HIF-1 upon hypoxia

Abstract

As a famous tumor suppressor, p53 is also activated under hypoxic conditions. Hypoxia-inducuble factor 1, HIF-1, is involved in the activation of p53 upon hypoxia. However, how p53 is modulated by the HIF-1 pathway to decide cell fate is less understood. In this work, we developed a network model including p53 and HIF-1 pathways to clarify the mechanism of cell fate decision in response to hypoxia. We found that HIF-1α and p53 are activated under different conditions. Under moderate hypoxia, HIF-1α is activated to induce glycolysis or angiogenesis, and promotes partial accumulation of p53 by inducing PNUTS. Under severe hypoxia, p53 rises to high levels due to ATR-dependent stabilization and promotes Mdm2-dependent HIF-1α degradation. As a result, fully activated p53 triggers apoptosis. Of note, competition for p300 between HIF-1α and p53 plays a key role in regulating their transcriptional activities. This work may advance the understanding of the mechanism for p53 regulation by HIF-1 in the hypoxic response.