BioWorld International Correspondent
LONDON - Genetic studies of the worm Caenorhabditis elegans have turned up a novel mechanism for regulation of p53, the protein that is mutated in more than half of all human cancers.
No one knows if there is a similar mechanism in human cells - but if there is, it could provide a good target for new cancer therapies aimed at up-regulating p53 signaling.
Anton Gartner, Cancer Research UK career development award fellow at the University of Dundee in Scotland, told BioWorld International: "There are thousands of scientists worldwide working on the regulation of human p53. This study is important because it highlights a novel mechanism by which p53 is regulated, which might also exist in humans." Much more work will be required, he added, but he hopes the latest findings will open up new avenues of research into how cancer develops.
Gartner, who was working at the Max Planck Institute for Biochemistry in Martinsried, Germany, when he carried out the study, published a report of the work in the Feb. 11, 2005, issue of Cell. The paper is titled "Translational Repression of C. elegans p53 by GLD-1 Regulates DNA Damage-Induced Apoptosis." Gartner's co-authors are from the Max Planck Institute, Washington University School of Medicine in St Louis and the University of Zurich in Switzerland.
In humans, p53 plays a role in tumor development: Most human cancers have found ways to escape from the ability of the protein to clamp down on cell division and to trigger apoptosis of abnormal cells. As a result, tumor cells divide uncontrollably.
Gartner's team set out to find previously unknown pathways and mechanisms for the regulation of p53, using C. elegans as a model. They, and others, previously had established that C. elegans has a primitive p53-like pathway that directs cells toward apoptosis. The name of the primordial p53-like gene is cep-1.
They searched for mutant worms whose germ cells had higher levels of p53/cep-1-dependent apoptosis than wild-type animals. Then the hunt started to locate the mutation in the organism's genome.
Having narrowed the affected gene down to one of 10, Gartner and colleagues found a point mutation in a gene called GLD-1. The mutation is called op236.
Gartner said: "We knew that this gene, GLD-1, affected apoptosis, and we knew that this apoptosis was p53 dependent. What we then had to do was to make the molecular connection between p53 regulation in the worm and GLD-1."
Previous studies on GLD-1 suggested that the product of the gene might have its effect by repressing translation of target genes involved in various developmental processes.
"This, of course, led us directly to ask the question, does GLD-1 repress translation of worm p53? In the paper in Cell, we show that this is indeed the case," Gartner said. Their experiments showed that the wild-type GLD-1 but not the mutant form bound directly to the messenger RNA produced by the cep-1/p53 gene, so repressing translation.
Whether that finding can be turned to advantage for the development of cancer therapies is impossible to say. However, GLD-1 does have a homologue in mammals called Quaking.
Gartner said: "Scientists working in this field need to find out first if this mechanism of p53 regulation is conserved in humans. But even if it turns out that Quaking does not directly repress p53 translation in humans, it will be important to determine whether human p53 is translationally repressed by another mechanism, and assess the potential importance of this."
Most cancer treatments, he added, depend on instructing tumor cells to undergo apoptosis or to stop dividing. So the up-regulation of p53 activity generally is beneficial. One way of achieving that would be to block translational repression of p53, Gartner concluded.
The work fits with other studies into proteins in the same family as GLD-1. Those have shown that related proteins in other species similarly regulate several different target messenger RNAs.
Lesley Walker, director of cancer information at Cancer Research UK, said: "We know that p53 is a crucial gene in the development of cancer, and any information on how it is regulated helps us to understand cancer better."