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.
Highlights
Hypoxia has frequently been described to be a p53 inducer.[7]
The p53 pathway is inactivated in most tumours because it functions as the ‘guardian of the genome’.2 p53 acts as a tetrameric transcription factor that induces the transcription of hundreds of target genes, which are involved in regulating apoptosis, cell cycle and DNA repair among others.[3]
P53 is kept at very low levels by MDM2-mediated ubiquitination and subsequent proteasomal degradation,[5,6] while it is stabilised by various cellular stresses
Summary
According to the severity and duration of hypoxia, as well as to the cell line, the effects of the oxygen deficiency on p53 can be different. HIF-1a stabilisation leads to the transcription of target genes involved in growth of blood vessels such as VEGF, inducible nitric oxide synthase, fibroblast growth factor and matrix metalloproteinases.[1] The notion that p53 has a role in limiting tumour vascularisation has come from a number of clinical studies showing correlations between mutated p53, greater VEGF levels and microvessel density.[118] At least three mechanisms are used by p53 to inhibit angiogenesis It increases the production of antiangiogenic factors[118] among them, is thrombospondin-1. P53 transcriptionally represses genes encoding proangiogenic factors, including VEGF and basic fibroblast growth factor.[119,120]
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