BioWorld International Correspondent

LONDON - A trawl through the entire genome of the fruit fly identified a multitude of enzymes thought to play a role in the regulation of cell division. Because all of them have equivalents in humans, and because many are defective in diseases such as cancer, the study has provided scientists with new leads for cancer drugs.

Monica Bettencourt-Dias, a research associate in the department of genetics at the University of Cambridge in the UK, told BioWorld International: "Cell division is such an important process, and it goes wrong in so many different diseases, that it is very important to know who the different players are. This study has allowed us to find novel molecules that are involved in regulating this process - and which may not be well-regulated in cancer, for example - as well as giving us new insights into how the process of cell division is regulated."

One satisfying aspect of the study, she added, was the ability to do the work using the fruit fly, Drosophila melanogaster, and then to be able to extrapolate the findings to humans.

David Glover, professor of genetics at the University of Cambridge (Bettencourt-Dias works in his lab), told BioWorld International: "This study offers the opportunity to identify potential new targets that one can use in the development of drugs for treatment of proliferative diseases. It is as though we have added a whole load of new pieces to the jigsaw puzzle in a single study."

Glover and his colleagues, together with collaborators at Dundee, UK-based Cyclacel Group plc, reported the study in the Dec. 23, 2004, issue of Nature in a paper titled "Genome-wide survey of protein kinases required for cell cycle progression."

The study is part of a larger program supported by Cancer Research UK in which model organisms are used to study the basic aspects of cell division. It focused on the Drosophila genes that encode protein kinases, enzymes that add phosphate groups onto proteins, leading to a change in the protein's structure or function.

Protein kinases, then, are of key interest to scientists trying to develop cancer therapies, because the cell-division cycle is controlled primarily by cycles of phosphorylation and dephosphorylation of proteins.

Significantly for researchers, the process of cell division has remained essentially unchanged throughout evolution: Exactly the same protein kinases regulate cell division in the fruit fly as they do in humans. Although humans have many more protein kinases than Drosophila does, they are duplications of genes that exist in Drosophila, rather than entirely new ones.

Making full use of the entire sequence of the genome of D. melanogaster, the team's approach was to down-regulate each of the genes encoding the fly's 228 protein kinases. There is a highly efficient way of doing that on D. melanogaster cells in culture, using the technique of RNA interference. Out of 228 protein kinases examined in that way, 80 had some impact on the progression of the cell cycle.

"From these results, we have been able to identify a series of novel protein kinases that have never been characterized before, as well as protein kinases that have never been shown to have the functions that we can now ascribe to them," Glover said. "We want to study these to improve our understanding of cell biology, and we will look at human tumor cells to see how these processes become perturbed."

Glover also is chief scientist of the Cambridge-based Polgen Division of Cyclacel Ltd. Earlier work in Glover's laboratory identified two groups of protein kinases using the fruit fly model, the Aurora kinases and the Polo kinases. The counterparts of those in humans now are known to play a role in regulating cell division, and to malfunction in a high proportion of human tumours.

Cyclacel has identified a series of small-molecule inhibitors of the Aurora enzymes. Tests in the laboratory have shown that they can kill a range of tumor cell types. Glover said preclinical studies showed that the Aurora inhibitors can "dramatically" reduce tumor growth in animals. Cyclacel also has small-molecule inhibitors of the Polo kinases still in the discovery phase.

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