New regulatory mechanism of p53 stability revealed
Cancer Research UK Edinburgh Centre scientists discover novel mechanism of regulation of p53 – an important tumour suppressor protein: July 2018
The p53 tumour suppressor protein encoded by the TP53 gene in humans has been described as "the guardian of the genome" because of its ability to trigger self-destruction of cancerous cells and its role in preventing genome mutations that can lead to cancer. In fact, the TP53 gene is the most frequently mutated gene (>50%) in human cancer. Mutations in p53 are found in most tumour types, and so contribute to the complex network of molecular events leading to tumour formation.
Considering that inactivation of p53 functions is an almost universal feature of human cancer cells, the mechanisms of regulation and activities of this protein were intensely studied over the years. Many have considered the p53 protein “the Achilles heel of the tumour” and tremendous effort was put to develop p53 based cancer therapies. Some of them are already in clinical use, others in clinical trials or at earlier stages of development.
Unfortunately, despite years of investigations, the mechanisms controlling p53 behaviour in cells are still incompletely understood. This is one of the main obstacles in more efficient development of p53-linked therapeutic approaches.
In recent work by Rodriguez et al. entitled “PHD3 regulates p53 protein stability by hydroxylating Proline 359” that has been published in the journal “Cell Reports”, the researchers from the Cancer Research UK Edinburgh Centre and their collaborators led by Dr Alexander von Kriegsheim provide important new insights into p53 function by describing previously unknown mechanism of regulation of p53 stability in cells. The scientists demonstrated that p53 is a substrate of prolyl hydroxylase 3 (PHD3) – an enzyme introducing a hydroxyl group (-OH) into amino acid proline - and that hydroxylation by PHD3 regulates p53 protein stability through modulation of ubiquitination – a process that marks proteins for degradation.
These discoveries shed new light on the complexity of p53 signalling and might guide future developments in the field of p53 based cancer therapeutics.
Article in the “Cell Reports”: https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31050-7
Network Biology and Proteomics Group web page: https://www.ed.ac.uk/cancer-centre/research/von-kriegsheim-group
Overview of p53 functions: https://www.cell.com/cell/pdf/S0092-8674(17)30953-4.pdf
Overview of p53-based Cancer Therapy: http://cshperspectives.cshlp.org/content/2/9/a001222.long