Tumor suppression by p53: fall of the triumvirate?

p53 is a key tumor suppressor protein that has numerous functions. Its primary mode of action has generally been ascribed to the induction of cell-cycle arrest, apoptosis, or senescence upon stress. Li et al. challenge this dogma with evidence that all three of these programs are dispensable for p53's tumor suppressive role

The role of ubiquitin modification in the regulation of p53

The p53 tumor suppressor protein is involved in regulating a wide variety of stress responses, from senescence and apoptosis to more recently discovered roles in allowing adaptation to metabolic and oxidative stress. After 34 years of research, significant progress has been made in unraveling the complexity of the p53 network, and it is clear that the regulation of p53 protein stability is critical in the control of p53 activity. This article focuses on our current understanding of how the level and activity of p53 is controlled by this seemingly simple mechanism. This article is part of a Special Issue entitled: Ubiquitin–Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf

Small molecules that bind the Mdm2 RING stabilize and activate p53

p53 is a tumour suppressor that responds to a variety of stresses such as oncogenes and DNA damage by activating its transcriptional targets to allow repair or elimination of damaged cells. In the absence of stress signals p53 needs to be kept in check and this is achieved by the E3 ligase MDM2. For tumours that retain wild-type p53 therapeutic strategies aimed at removing the inhibitory activity of MDM2 on p53 are under development, and to date have focused on drugs that prevent the binding of p53 to MDM2. Here we report the analysis of a group of synthetic analogues derived from 5-deazaflavin compounds previously identified in a screen as inhibitors of MDM2 autoubiquitination. Using measurement of surface plasmon resonance we demonstrated that active 5-deazaflavin analogues bind to the MDM2 RING, while inactive compounds show no binding. In cellular assays, these active MDM2 RING binding compounds inhibited the ubiquitination of p53, stabilized p53, led to increased expression of p53 targets and caused corresponding cell cycle effects. Deazaflavin analogues therefore function to activate p53 through a novel mechanism, by inhibiting the E3 ligase activity of MDM2 in a manner that involves binding to the MDM2 RING

The relationship between air pollution and all-cause mortality in singapore

10.3390/ATMOS11010009Atmosphere111