Sustained and pulsatile increases in p53 protein differentially regulate stress responses.
Major finding: Sustained and pulsatile increases in p53 protein differentially regulate stress responses.
Approach: p53 dynamics were modified with drug treatment, and the response to γ-irradiation was assessed.
Impact: Therapeutic modulation of p53 protein dynamics may promote tumor cell death or senescence.
In response to stress, p53 mediates transient cell-cycle arrest or terminal fates, such as apoptosis or senescence, and its activity is regulated at multiple levels to control downstream signaling. Purvis and colleagues describe an additional mode of p53 regulation via alterations in its protein dynamics. Different types of radiation damage are known to affect the frequency and amplitude of p53 protein level fluctuations and can induce either pulsed or sustained p53 pathway activation. The authors tested whether perturbing these dynamics using the p53 inhibitor Nutlin-3 altered the downstream cellular response to γ-irradiation, which normally induces repeated p53 pulses and leads to cell-cycle arrest. Using a mathematical model, the authors identified the optimal concentration and timing of Nutlin-3 treatment necessary to achieve a constant level of p53 signaling. In contrast with pulsed p53 signaling, which activated genes involved in cell-cycle arrest, DNA repair, and p53 regulation, sustained p53 signaling induced by sequential Nutlin-3 treatments led to continuous upregulation of these genes as well as an increase in the expression of a subset of apoptosis and senescence marker genes. In addition, sustained p53 levels resulted in increased β-galactosidase positivity and a reduction in cell division in response to γ-irradiation, indicative of senescence. These results suggest that sustained p53 levels accelerate commitment to senescence following this type of DNA damage and that protein dynamics contribute to the modulation of p53 signaling specificity. Although additional work is needed to investigate the interplay between these dynamics and posttranslational p53 modifications, targeted manipulation of p53 protein dynamics may represent a novel therapeutic strategy to induce apoptosis or senescence in cancer cells.
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