p53 Tumour Suppressor Protein

The Cell Transformation Unit at the CMRI is interested in the p53 tumour suppressor protein.  Projects include studies on how p53 “works”; how another cancer related protein called YB-1 affects p53 function; and whether natural human p53 variants influence cancer onset and other aging-related parameters.  Each project outlined below covers this broad area and is underpinned by some of the ‘key’ and ‘recent’ publications.

Importance of the proline domain in p53 dependent apoptosis
Importance of the proline domain in tumour suppression by p53
Disease predisposition and p53
Interactions between Y-box binding protein YB1 and p53
p53 and other genes associated with cellular immortalization

Importance of the proline domain in p53 dependent apoptosis

The process by which p53 prevents cancers forming is unknown at this stage, however, research suggests that the ability of p53 to kill cells is likely to be the most important mechanism.  This cell death process, inititated by p53, is called ‘apoptosis’.  A section of the p53 protein containing large quantities of the amino acid proline has been identified as the region of p53 that controls the cell-killing activity.  Our research is investigating whether removing this region of p53 affects cell life span.

Back to Top

Importance of the proline domain in tumour suppression by p53

We have constructed an animal model homozygous for a deficiency in the proline block of the p53 gene.  This research will provide valuable information on the effect of the proline-block on the incidence of tumour development.

Back to Top

Disease predisposition and p53

We have been analysing a large group of individuals about which a great deal of information is known concerning their health.  We have determined the type of p53 present in each individual in this group.  There are two common forms of p53 in humans, one having a proline at position 72 in the protein, and the other having the amino acid arginine.  Some people have two p53 gene copies with arginine, some with two copies of the proline form and some have both (one on each chromosome).  To date, we have found that those with the arginine form of p53 are more likely to have lung dysfunction if they smoke, but show no difference if they do not.  We will continue to analyse these individuals with the aim of determining any association between p53 genotype and any physiological disorders resulting from life-style or environmental factors.  This project is therefore studying gene-environment interactions.

Back to Top

Interactions between Y-box binding protein YB1 and p53

YB-1 is a multi functional protein that can promote cancer formation and is highly expressed in advanced cancers.  Interestingly, YB-1 binds to p53.  YB-1 is located in the cytoplasm of cells but upon stress treatment can translocate to the nucleus and function as a transcription factor, regulating gene expression.  We have shown that p53 helps YB-1 shift to the nucleus where it can prevent p53 dependent apoptosis.  We have also shown that inhibition of YB-1 leads to cell death that requires p53.  We are continuing to study the interactions between YB-1 and p53 to understand how they affect each other, with the goal of using YB-1 as a new therapeutic target in the treatment of cancer.

Back to Top

p53 and other genes associated with cellular immortalization

In collaboration with the Cancer Research Unit, we are studying the interplay between p53 and another tumour suppressor gene, p16INK4a.  Both proteins encoded in these genes contribute to cell immortalisation primarily through loss of their normal functions.  Interactions between p53 and p16INK4a are currently of interest to us, especially in breast epithelial cells (the cell type that gives rise to breast cancer) as they appear to negatively regulate each other.

Back to Top