Crosstalk Between Mdm2, p53 and HIF1-α: Distinct Responses to Oxygen Stress and Implications for Tumour Hypoxia

Abstract

The E3 ubiquitin ligase Mdm2 regulates two transcription factors, p53 and HIF1α, which appear to be tailored towards different and specific roles within the cell, the DNA damage and hypoxia responses, respectively. However, evidence increasingly points towards the interplay between these factors being crucial for the regulation of cellular metabolism and survival in times of oxygen stress, which has particular relevance for tumour formation. Mdm2, p53 and HIF1α all respond to hypoxia, and intriguingly, have distinct roles depending on the level of hypoxia. The data from numerous studies across different conditions hint at the interplay between these key factors in cellular homeostasis. Here we try to weave these strands together, to create a picture of the complex tapestry of interactions that demonstrates the importance of the crosstalk between these key regulatory proteins during hypoxia.

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

“…The resulting decrease in TP53 restrains apoptosis and can favor angiogenesis by limiting angiostatic gene expression, such as Thrombospondin-1 (Dameron et al, 1994). It is worth noting that TP53 and HIF1-α can compete for binding to MDM2, which means that under hypoxia HIF1-α could restrain the capacity of MDM2 to inhibit TP53 (Robertson et al, 2014).…”

Current relevance of hypoxia in head and neck cancer

“…Thus far it has been thought that inhibiting the MDM2/HIF-1alpha interaction would result in tumor cell death in hypoxia [147] but recently Joshi et al [84] found that MDM2 causes HIF-1alpha to be degraded during hypoxia so inhibiting the MDM2/HIF-1alpha interaction may actually result in tumor growth, not death. The role of p53 and its mutations can be regarded as well established in HNSCC, however its precise interrelationship with tumor hypoxia needs to be explored and clarified further.…”

Phosphorylation of murine double minute‐2 on Ser 166 is downstream of VEGF‐A in exercised skeletal muscle and regulates primary endothelial cell migration and FoxO gene expression

“…Mdm2 can indeed regulate the activity of other transcription factors, such as HIF‐α and FoxO (11, 12). VEGF‐A is a well‐established target of HIF‐1α (21).…”

“…Mdm2 can sense endogenous and exogenous stresses through posttranslational modifications, such as site‐specific phosphorylation, that in turn control Mdm2 activity and recruitment of downstream targets (5, 10). For example, phosphorylation on Ser 166 in response to insulin‐like growth factor‐1 promotes degradation of p53 and HIF‐1α stabilization in tumor cells (11). Mdm2 also binds to FoxO proteins (12).…”