Fig. 10.

Paradigm of p53 regulation by PEPD. PEPD binds to both nuclear and cytosolic p53. More than 50% of cellular p53 is sequestered by PEPD, rendering cells dependent on PEPD for survival and growth under normal circumstances, as eliminating PEPD activates p53, which leads to cell death. PEPD binds to nuclear p53 to inhibit its phosphorylation and transcription activity. PEPD competes with MDM2 for p53 binding, thereby inhibiting MDM2-dependent mitochondria translocation of nuclear and cytoplasmic p53, leading to inhibition of transcription-independent activity of p53. The PEPD-p53 complex is designed for rapid mobilization of pre-synthesized p53 in response to stress, which is mediated by ROS. Notably, MDM2 is known to promote p53 translocation to mitochondria by monoubiquitinating p53, to promote p53 degradation by polyubiquitinating p53, and to inhibit p53 transcription activity unrelated to ubiquitination. It is also known that the MDM2 gene is transcriptionally activated by p53