CSB modulates the competition between HIF-1 and p53 upon hypoxia

Abstract

Both hypoxia-inducible factor-1 (HIF-1) and tumor suppressor p53 are involved in the cellular response to hypoxia. It has been reported that HIF-1α induces cockayne syndrome B (CSB) to compete with p53 for limited p300. We developed a network model to clarify how the interplay between HIF-1 and p53 modulates cellular output in the presence of CSB. Our results revealed that HIF-1α is progressively activated depending on the severity of hypoxia. Activated HIF-1α promotes its own activation by inducing CSB to dissociate p300 from p53 under moderate hypoxia; in severe hypoxia, p53 accumulates remarkably due to ATR-dependent phosphorylation and wins the competition for p300. As a result, HIF-1α induces PFKL and VEGF to facilitate cellular adaptation to mild and moderate hypoxia respectively, while p53 is activated to induce apoptosis under severe hypoxia. This work may advance the understanding of the modulation of the interplay between HIF-1 and p53 in the hypoxic response.

Keywords: p53; CSB; HIF-1α; hypoxia; network model.