Oscillations of the p53-Akt Network: Implications on Cell Survival and Death

Keng Boon Wee,Baltazar D Aguda,Uttam Surana,Mark R Cookson

doi:10.1371/journal.pone.0004407

Abstract

Intracellular protein levels of p53 and MDM2 have been shown to oscillate in response to ionizing radiation (IR), but the physiological significance of these oscillations remains unclear. The p53-MDM2 negative feedback loop – the putative cause of the oscillations – is embedded in a network involving a mutual antagonism (or positive feedback loop) between p53 and AKT. We have shown earlier that this p53-AKT network predicts an all-or-none switching behavior between a pro-survival cellular state (low p53 and high AKT levels) and a pro-apoptotic state (high p53 and low AKT levels). Here, we show that upon exposure to IR, the p53-AKT network can also reproduce the experimentally observed p53 and MDM2 oscillations. The present work is based on the hypothesis that the physiological significance of the experimentally observed oscillations could be found in their role in regulating the switching behavior of the p53-AKT network between pro-survival and pro-apoptotic states. It is shown here that these oscillations are associated with a significant decrease in the threshold level of IR at which switching from a pro-survival to a pro-apoptotic state occurs. Moreover, oscillations in p53 protein levels induce higher levels of expression of p53-target genes compared to non-oscillatory p53, and thus influence cell-fate decisions between cell cycle arrest/DNA damage repair versus apoptosis.

Highlights

In response to DNA damage from exposure to ultraviolet (UV) or ionizing radiation (IR), damped oscillations in the levels of p53 and MDM2 proteins have been observed in populations of cells such as fibroblasts and MCF7 breast cancer cells [1,2]
Another assumption made is that k0 and dMDM2a are directly proportional to IR intensity (r), that is, k0 = k0,basal+k0,IR*r and dMDM2a = dMDM2a,basal+dMDM2a,IR*r
The justification of this assumption is based on the many known pathways associated with IR-induced DNA damage that upregulate p53 and down-regulate MDM2

Summary

Introduction

In response to DNA damage from exposure to ultraviolet (UV) or ionizing radiation (IR), damped oscillations in the levels of p53 and MDM2 proteins have been observed in populations of cells such as fibroblasts (human and mouse) and MCF7 breast cancer cells [1,2]. Isolated single cells exhibit oscillations that are more sustained, sometimes lasting more than three days, depending on the persistence of DNA damage [3] The frequencies of these oscillations generally increase with increasing IR intensity, and oscillation periods are typically in the range of 4 to 7 hrs; unlike this narrow range in the observed periods, the amplitudes of p53 oscillations are quite variable. Because it is the number of oscillations rather than their amplitudes that is observed to be dependent on the dose of IR, p53 oscillations have been described as ‘digital’. Similar observations have been observed in vivo in mouse intestine and spleen [4] where damped p53 pulses with periods of 4.5 to 6 hrs are reported

Methods

Results

Conclusion