期刊
FEBS LETTERS
卷 593, 期 18, 页码 2596-2611出版社
WILEY
DOI: 10.1002/1873-3468.13525
关键词
cell fate decision; HIF-1 alpha; hypoxia; network model; p53 activation
资金
- National Natural Science Foundation of China [11574139, 11874209]
- Fundamental Research Funds for the Central Universities [14380013, 14380015]
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-1 alpha and p53 are activated under different conditions. Under moderate hypoxia, HIF-1 alpha 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-1 alpha degradation. As a result, fully activated p53 triggers apoptosis. Of note, competition for p300 between HIF-1 alpha 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.
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