Redox regulation of the tumor suppressor p53

Abstract

The work presented in this thesis mainly focuses on how redox signaling controls the tumor suppressor p53. We uncovered that redox signaling could activate p53 independent of, but also in synergy with DNA damage signaling. Importantly, our observation that redox signaling can activate p53 without inducing DNA damage and the downstream DDR, challenges the dogma that ROS-induced p53 activation is an indirect effect of oxidative DNA damage and emphasizes the importance of redox signaling in controlling p53 activity. We provide evidence that p53 can be regulated by redox signaling through multiple levels: upstream redox signaling that induces activation of stress-activated kinases and oxidation of cysteines in p53 itself. For the first time, we show that p53 cysteine oxidation leads to the formation of intermolecular disulfide-dependent protein complexes with other regulatory proteins. Understanding redox control of p53 like described in this thesis and beyond helps to understand fundamental processes in cancer biology that may lead to new ideas for cysteine-directed anti-cancer therapies.