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

Area of Science:

• Molecular Biology
• Cellular Biology
• Biochemistry

Background:

• Hypoxia-inducible factor-1 (HIF-1) and tumor suppressor p53 are key regulators of cellular response to low oxygen conditions.
• Cockayne syndrome B (CSB) has been implicated in the competition between HIF-1α and p53 for the p300 coactivator.

Purpose of the Study:

• To elucidate the regulatory network governing the interplay between HIF-1 and p53 in the context of CSB during hypoxia.
• To understand how varying degrees of hypoxia influence the competition for p300 and subsequent cellular outcomes.

Main Methods:

• Development of a computational network model to simulate the interactions between HIF-1, p53, CSB, and p300.
• Analysis of the model's predictions under different hypoxia severities.

Main Results:

• HIF-1α activation is progressive with increasing hypoxia severity.
• Under moderate hypoxia, HIF-1α induces CSB to sequester p300, promoting HIF-1α activity.
• Under severe hypoxia, ATR-dependent p53 phosphorylation leads to its accumulation, enabling it to outcompete HIF-1α for p300.

Conclusions:

• The interplay between HIF-1 and p53, modulated by CSB, dictates cellular fate under hypoxia.
• HIF-1α drives adaptation via PFKL and VEGF induction in mild to moderate hypoxia.
• p53 activation leads to apoptosis in severe hypoxia, representing a critical switch in cellular response.