Caspases not necessary for mammalian apoptosis

Anaheim, Calif. - More than 30 years after the term apoptosis was coined, researchers are just beginning to understand the role of caspases in this process, despite a flurry of recent research.

"It used to be thought that most cells die because they're injured or damaged, whereas now it's clear that most cells die because they activate a cell suicide mechanism whose very purpose is to cause the death of a cell. In 1972, the term apoptosis was coined for this particular morphology of cell suicide."

"But since the late 1980s, as the mechanisms of cell death became understood, there's been an avalanche in publications. There are now about 300 publications on cell death appearing every week. So we know a lot about the mechanisms, but there's still a lot of confusion and contradictory results in the field," Dr. Vaux says.

One area in which researchers' understanding continues to evolve is the role of caspases.

"Caspases are cysteine proteases that cleave protein after particular aspartic acid residues. Within virtually all the cells of the body, caspases exist in an inactive state. But they can become activated and eventually cause the cell to digest from within," he says.

Work on programmed cell death in the nematode Caenorhabditis elegans won a Nobel Prize in 2002 (http:// http://nobelprize.org/medicine/laureates/2002/horvitz-lecture.html).

"That work showed that caspases are essential for programmed cell death in the worm," Dr. Vaux explains. "Because mammals also possess caspases, it's been assumed that caspases would be essential for suicide of mammalian cells as well. But it's turned out to be more complicated in mammals. It's clear that caspases can be sufficient to cause cell death in mammalian cells. So activation of caspases might be useful in killing cancer cells.

"But it's also been made clear by recent studies on gene-knockout mice that caspases in mammalian cells aren't required for those cells to commit suicide."

Among the findings Dr. Vaux considers most surprising is the finding that in mice lacking BAX and BAK genes, no apoptosis occurs (MC Wei et al. Science. 2001 Apr 27;292(5517):727-730.).

"In mice lacking those two genes," he says, "There's no apoptosis. Most of the mice die in utero. But some of them can live to adulthood and look pretty much normal. So that means all of the cell death that's required for creation of tubes, formation of correct morphology and to allow the right number of blood cells to exist, and even to allow skin to be produced and function normally, does not require any apoptosis. But it also means there must be some other mechanism by which the cells can kill themselves. It appears there are important differences between cell death in the worm and cell death in mammals."

Laboratory assays of caspase activation as a measurement of cell death can help researchers distinguish which cells died by that mechanism.