Oncogenic alterations in the p53 pathway abolish oscillatory competence

Abstract

AbstractThe tumor suppressor p53 displays concentration oscillations in response to DNA damage, a behavior that has been suggested to be essential to its anti-cancer function. Many genetic alterations in the p53 pathway have been shown to be oncogenic, whether by experiment or by clinical associations with various cancers. These oncogenic alterations include somatic mutations, copy number variations and inherited polymorphisms. Using a differential equation model of p53-Mdm2 dynamics, we employ Hopf bifurcation analysis to show that all of the oncogenic perturbations have a common effect, to abolish the oscillatory competence of p53, thereby impairing its tumor suppressor function. In this analysis, these diverse genetic alterations, widely observed in human cancers, have a unified mechanistic explanation.SignificanceIn human cancers, the p53 tumor suppressor pathway is frequently altered by diverse genetic changes. An integrated understanding of these oncogenic alterations is currently lacking. We show that all oncogenic alterations in the p53 pathway abolish the oscillatory competence of p53, a property that is essential for cell cycle arrest upon stress, for effective DNA damage response and for maintaining genome integrity. This unified dynamical explanation of distinct cancer driver events that converge on a key cancer hallmark pathway has practical implications for anti-cancer therapies.