Gene May Hold Key to Future Cancer Therapies

Cells divide creating new cells as part of the body's natural growth, renewal, and healing mechanisms but cancer results when cells divide in an uncontrolled way. What the Manchester investigators have found is that a protein in our cells called "Bub 1” is needed for normal cell division to take place; if the gene that generates Bub 1 is inactivated then the cells are unable to divide successfully.

"Bub 1 is an enzyme that controls several processes required for cell division to occur,” said Dr. Stephen Taylor, who led the research in the UM faculty of life sciences. "We have shown that mouse embryos lacking the Bub 1 gene are unable to develop. Older cell types also failed to divide when the gene is switched off, while male mice lacking Bub 1 became infertile as their sperm cells died.”

In reality, turning off Bub 1 had such a profound effect on cell division at all stages of a cell's life--known as the ‘cell cycle'--that the researchers are confident it will have a similar effect on cancer cells. "Before cells can divide they have to duplicate and then distribute their genetic material so that the two ‘daughter' cells receive all the genetic information for further growth and development,” said Dr. Taylor. "The distribution phase has to be done with a high degree of accuracy--just one chromosome segregated incorrectly, for instance, leads to Down's syndrome--so the cell has a surveillance mechanism which acts as a brake to delay chromosome segregation until accuracy has been guaranteed.”

A fundamental part of this intricate surveillance system is Bub 1. The team discovered that when the gene is deactivated, the surveillance mechanism fails and accuracy is lost, resulting in cell death. Now, that scientists understand the precise role of Bub 1 in normal cell division, as well as what goes wrong when the gene is missing, they plan to evaluate their hypothesis on cancer cells. "Unlike some other genes that become mutated in cancer cells, the Bub 1 gene appears normal indicating that it behaves in exactly the same way in cancer cells as it does in healthy cells. If this is the case, then we can be confident that switching it off will stop cancer cells proliferating too. And while our normal cells don't divide that often, cancer cells divide more frequently, so hopefully by targeting Bub1 we will selectively kill cancer cells.”

Just as exciting, according to Dr. Taylor, is the fact that drugs are already being developed that are able to block the actions of Bub 1-type enzymes, known as protein kinases; such kinase blockers (inhibitors) are already providing a whole new approach to fighting cancer, and Bub1 inhibitors may be another weapon in the oncologist's arsenal.

The research begun in 1999, was published in the October 9, 2007, issue of the journal Developmental Cell.


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