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David W Meek
Reader
Regulation of the p53 tumour suppressor network
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E-mail: d.w.meek@dundee.ac.uk Tel. 01382 660111 ex. 33517
The core theme of the research carried out in my laboratory is to understand the molecular signalling events that regulate the p53 network in the context of normal physiology and in the development of cancer. Our aims are summarised as follows.
Aims of the Research
- To understand the molecular basis of the signalling mechanisms that regulate the p53 response.
- To determine whether the signalling events regulating p53 are modulated or changed during tumorigenesis in a manner that would inhibit the ability of the p53 network to carry out its protective function of eliminating genetically damaged cells.
- To explore specific signalling interactions with a view to determining their potential as targets for novel therapeutic intervention in the treatment of cancer.
BACKGROUND TO OUR WORK
The p53 network
The p53 tumour suppressor protein is a potent transcription factor which stimulates the expression of a host of genes involved in growth arrest, apoptosis, DNA repair, and inhibition of angiogenesis, invasion and metastasis. p53 also is able to repress the expression of a different set of genes including those involved in mediating or stimulating cell division. A growing body of evidence now also suggests that p53 may have a transcriptionally independent role in apoptosis as a functional homologue of the BH3-only proteins.
Mdm2 and the activation of p53
Under normal circumstances, p53 is kept under tight control through its partnership with Mdm2, a ubiquitin E3 ligase that mediates the ubiquitylation and degradation of p53. In response to a range of different cellular stresses, the p53-Mdm2 interation is interrupted with the outcome that p53 degradation (and in some cases ubiquitylation) is blocked. The p53 protein is thus able to accumulate rapidly following stress leading to a change in the balance of gene expression that favours growth arrest or apoptosis (see the figure). We are interested in the mechanisms by which the induction of p53 is regulated and the signalling events through which its ability to influence cellular fate is finely tuned.
p53 and cancer
During tumorigenesis, p53 function is eliminated thereby removing the cell’s protective mechanism against genetic damage and hyper-proliferation. This can occur through a number of routes but mainly through mutations occuring in the gene encoding p53 itself. Alternatively, p53 dysfunction can occur through changes in key regulators of p53: for example, over-production of Mdm2 in tumours is though to suppress p53 activation. Understanding the mechanisms that regulate p53 function may therefore provide a clearer picture of how p53 inactivation can occur during cancer development. Additionally, these pathways may provide novel targets for tailored drug development aimed at restoring p53 function in tumour cells.
Molecular signalling through phosphorylation/dephosphorylation
mechanisms
Both p53 and Mdm2 (together with other key components of the network) are controlled through a series of regulatory post-translational modifications including modification by phosphorylation and dephosphorylation. Phosphorylation reactions are carried out in the cell by a family of enzymes called protein kinases and are dephosphorylated by protein phosphatases. Both p53 and Mdm2 are subject to multi-site phosphorylation where different protein kinases/phosphatases, responsive to different signalling pathways, impinge on these target proteins with the outcome that a coordinated and integrated p53 response is achieved, depending on the cellular environment. For example, signals arising from DNA damage that bring about induction of p53 lead to the phosphorylation of p53 and Mdm2, activation of p53’s biochemical functions, and inhibition of Mdm2 activity. Our laboratory specialises in the study of these regulatory events.
A summary of our current knowledge of the molecular signals targeting both p53 and Mdm2 is shown in the figures below. These diagrams summarise work from many international research groups including our own.
Members of the Meek group in the Lab ...
Currently members of the group are (left to right on the photograph): Miranda Cox (Graduate Student), Lynsey McKenzie (Graduate Student), David Meek (Principal Investigator), Anna-Maria Ochocka (Post-doctoral Research Assistant) and Lynnette Marcar (Graduate Student).
... and in the field (or on the top of the mountain!!)
Collaborations
We have recently collaborated, or maintain ongoing collaborations, with colleagues both locally (within Dundee) and internationally. We welcome productive collaborations with other researchers working in areas of mutual benefit.
Current funding
Our work is currently funded by Cancer Research UK and the Association for International Cancer Research. We are indebted to each of these organisations for their support.
David Meek - Background and Publications
David Meek - Public understanding of science and fund raising
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