Unraveling p53 Dynamics

Science Signaling  24 May 2011:
Vol. 4, Issue 174, pp. ec149
DOI: 10.1126/scisignal.4174ec149

The tumor suppressor p53, which is activated by different forms of stress, mediates various cellular outcomes, including cell-cycle arrest, cell senescence, and cell death. Noting that DNA double-strand breaks (DSBs) caused by γ-irradiation or the drug neocarzinostatin (NCS) elicit a series of p53 “pulses” whose amplitude, duration, and frequency are independent of the amount of DNA damage, Batchelor et al. investigated the p53 response to ultraviolet (UV) irradiation, which leads to exposure of single-stranded DNA. Using a p53-Venus fusion protein to monitor p53 dynamics in individual cells, the authors determined that, unlike NCS, UV elicited a single pulse of p53 that increased in amplitude and duration with increasing UV dosage. The DNA damage response to DSBs is mediated through the kinase ATM, whereas that to UV is mediated through ATR. Both responses involve transmission of the damage signal to p53 and the consequent activation of negative feedback onto p53 through two loops (one involving the E3 ubiquitin ligase Mdm2, which targets p53 for proteasomal degradation, and one involving the phosphatase Wip1, which dephosphorylates p53, decreasing its stability). Noting that ATR activity doesn’t require its phosphorylation, the authors modified a model developed for the response to DSBs, which involved negative feedback from Wip1 to ATM. As modified for ATR (without feedback from Wip1 to ATR), the model predicted a single pulse of p53 with a duration that depended on UV dosage, a prediction that was consistent with Western analysis of ATR activity (based on substrate phosphorylation). Unlike the response to DSB, the p53 response to UV was not excitable, so that a transient input failed to elicit the full response. Noting that excitable behavior can result from rapid loss of an inhibitor, the authors determined that Mdm2 abundance decreased rapidly after γ-irradiation but not UV. Moreover, an Mdm2 mutant that could not be phosphorylated by ATM was not rapidly degraded in response to γ-irradiation, and expression of this mutant decreased the fraction of cells showing an excitable p53 pulse. Thus, different stimuli can lead to different p53 dynamics; these different dynamics can be explained by features of the underlying networks and, as the authors postulate, may contribute to the different cellular outcomes mediated by p53.

E. Batchelor, A. Loewer, C. Mock, G. Lahav, Stimulus-dependent dynamics of p53 in single cells. Mol. Syst. Biol. 7, 488 (2011). [PubMed]