UCLA

The tumor suppressor p53 oscillates in response to DNA double-strand breaks, a behavior that has been suggested to be essential to its anti-cancer function. Nearly all human cancers have genetic alterations in the p53 pathway; a number of these alterations have been shown to be oncogenic by experiment. These alterations include somatic mutations and copy number variations as well as germline polymorphisms. Intriguingly, they exhibit a mixed pattern of interactions in tumors, such as co-occurrence, mutual exclusivity, and paradoxically, mutual antagonism. Using a differential equation model of p53-Mdm2 dynamics, we employ Hopf bifurcation analysis to show that these alterations have a common mode of action, to abolish the oscillatory competence of p53, thereby, we suggest, impairing its tumor suppressive function. In this analysis, diverse genetic alterations, widely associated with human cancers clinically, have a unified mechanistic explanation of their role in oncogenesis.