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

FEBS Letters

article

Ping Wang¹  Di Guan¹  Xiao-Peng Zhang²  Feng Liu¹  Wei Wang¹ 

[1] National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University;Kuang Yaming Honors School, Nanjing University;Institute for Brain Sciences, Nanjing University

关键词: cell fate decision;    HIF-1a;    hypoxia;    network model;    p53 activation;   

DOI  :  10.1002/1873-3468.13525

来源: John Wiley & Sons Ltd.

【 摘 要 】

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-1a and p53 are activated under different conditions. Under moderate hypoxia, HIF-1a 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-1a degradation. As a result, fully activated p53 triggers apoptosis. Of note, competition for p300 between HIF-1a 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.

【 授权许可】

Unknown