Format

Send to

Choose Destination
Cell Rep. 2018 Jul 31;24(5):1316-1329. doi: 10.1016/j.celrep.2018.06.108.

PHD3 Regulates p53 Protein Stability by Hydroxylating Proline 359.

Author information

1
Systems Biology Ireland, University College Dublin, Dublin 4, Ireland; Cancer Research UK Edinburgh Centre, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
2
Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
3
Ludwig Institute for Cancer Research Ltd., SE-17177 Stockholm, Sweden; Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden.
4
Cancer Research UK Edinburgh Centre, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
5
Conway Institute, University College Dublin, Dublin 4, Ireland.
6
Systems Biology Ireland, University College Dublin, Dublin 4, Ireland; Cancer Research UK Edinburgh Centre, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK. Electronic address: alex.vonkriegsheim@igmm.ed.ac.uk.

Abstract

Cellular p53 protein levels are regulated by a ubiquitination/de-ubiquitination cycle that can target the protein for proteasomal destruction. The ubiquitination reaction is catalyzed by a multitude of ligases, whereas the removal of ubiquitin chains is mediated by two deubiquitinating enzymes (DUBs), USP7 (HAUSP) and USP10. Here, we show that PHD3 hydroxylates p53 at proline 359, a residue that is in the p53-DUB binding domain. Hydroxylation of p53 upon proline 359 regulates its interaction with USP7 and USP10, and its inhibition decreases the association of p53 with USP7/USP10, increases p53 ubiquitination, and rapidly reduces p53 protein levels independently of mRNA expression. Our results show that p53 is a PHD3 substrate and that hydroxylation by PHD3 regulates p53 protein stability through modulation of ubiquitination.

KEYWORDS:

EglN3; PHD3; USP7; hydroxylases; hypoxia; p53; proteomics

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center