Biomol Ther.  2017 Jul;25(4):396-403. 10.4062/biomolther.2017.086.

PIG3 Regulates p53 Stability by Suppressing Its MDM2-Mediated Ubiquitination

• Jin M
• Park SJ
• Kim SW
• Kim HR
• Hyun JW
• Lee JH

• KMID: 2386906
• DOI: http://doi.org/10.4062/biomolther.2017.086

Abstract

Under normal, non-stressed conditions, intracellular p53 is continually ubiquitinated by MDM2 and targeted for degradation. However, in response to severe genotoxic stress, p53 protein levels are markedly increased and apoptotic cell death is triggered. Inhibiting the ubiquitination of p53 under conditions where DNA damage has occurred is therefore crucial for preventing the development of cancer, because if cells with severely damaged genomes are not removed from the population, uncontrolled growth can result. However, questions remain about the cellular mechanisms underlying the regulation of p53 stability. In this study, we show that p53-inducible gene 3 (PIG3), which is a transcriptional target of p53, regulates p53 stability. Overexpression of PIG3 stabilized both endogenous and transfected wild-type p53, whereas a knockdown of PIG3 lead to a reduction in both endogenous and UV-induced p53 levels in p53-proficient human cancer cells. Using both in vivo and in vitro ubiquitination assays, we found that PIG3 suppressed both ubiquitination- and MDM2-dependent proteasomal degradation of p53. Notably, we demonstrate that PIG3 interacts directly with MDM2 and promoted MDM2 ubiquitination. Moreover, elimination of endogenous PIG3 in p53-proficient HCT116 cells decreased p53 phosphorylation in response to UV irradiation. These results suggest an important role for PIG3 in regulating intracellular p53 levels through the inhibition of p53 ubiquitination.

Keyword

PIG3; p53; MDM2; Ubiquitination; Apoptosis

MeSH Terms

Apoptosis
Cell Death
DNA Damage
Genome
HCT116 Cells
Humans
In Vitro Techniques
Phosphorylation
Ubiquitin*
Ubiquitination*
Ubiquitin