Reciprocal influence of the p53 and the hypoxic pathways

Abstract

When cells sense a decrease in oxygen availability (hypoxia), they develop adaptive responses in order to sustain this condition and survive. If hypoxia lasts too long or is too severe, the cells eventually die. Hypoxia is also known to modulate the p53 pathway, in a manner dependent or not of HIF-1 (hypoxia-inducible factor-1), the main transcription factor activated by hypoxia. The p53 protein is a transcription factor, which is rapidly stabilised by cellular stresses and which has a major role in the cell responses to these stresses. The aim of this review is to compile what has been reported until now about the interconnection between these two important pathways. Indeed, according to the cell line, the severity and the duration of hypoxia, oxygen deficiency influences very differently p53 protein level and activity. Conversely, p53 is also described to affect HIF-1α stability, one of the two subunits of HIF-1, and HIF-1 activity. The direct and indirect interactions between HIF-1α and p53 are described as well as the involvement in this complex network of their respective ubiquitin ligases von Hippel Lindau protein and murine double minute 2. Finally, the synergistic or antagonistic effects of p53 and HIF-1 on some important cellular pathways are discussed.

Figure 1

Schematic representation of the different pathways that have been proposed to explain the hypoxia-induced increase in p53 mRNA abundance, translation, p53 protein stability and activity as well as the hypoxia-induced decrease in p53 proteasomal degradation. ATM, ataxia-telangiectasia mutated; ATR, ataxia-telangiectasia mutated and Rad3-related; CHIP, carboxyl terminus of HSP70-interacting protein; HIF-1α, hypoxia-inducible factor-1α; MDM2, murine double minute 2; PNUTS, protein phosphatase-1 nuclear targeting subunit; PP1, protein phosphatase-1; pVHL, von Hippel Lindau protein; ROS, reactive oxygen species; Ub, ubiquitin

Figure 2

Schematic representation of the different pathways that have been proposed to explain the hypoxia-induced decrease in p53 gene transcription, p53 protein stability and activity as well as the hypoxia-induced increase in p53 protein degradation. CK2, casein kinase 2; HIF-1α, hypoxia-inducible factor-1α; HIPK2, homeodomain-interacting protein kinase 2; MDM2, murine double minute 2; NPM, nucleophosmin; ROS, reactive oxygen species; SIAH, seven in absentia homolog; Ub, ubiquitin; WSB-1, WD40-repeat/SOCS box protein

Figure 3

Schematic representation of the reciprocal modulation of HIF-1α, p53, pVHL and MDM2

Figure 4

Model for the regulation of p53 and HIF-1α protein level as well as of p53 and HIF-1 activity depending on the severity and the duration of hypoxia