"Normally, when telomeres get critically short, the cell commits suicide as a means of protecting the body," says Carol Greider, Ph.D., the Daniel Nathans chair of molecular biology and genetics at Johns Hopkins. Her study, appearing online this month at Cancer Cell, uncovers an alternate response where cells simply - and permanently - stop growing, a process known as senescence.
In an unusual set of experiments, the research team first mated mice with nonoperating telomerase to mice carrying a mutation that predisposed them to Burkitt's lymphoma, a rare but aggressive cancer of white blood cells. Telomerase helps maintain the caps or ends of chromosomes called telomeres, which shrink each time a cell divides and eventually - when the chromosomes get too short - force the cell to essentially commit suicide. Such cell death is natural, and when it fails to happen, the result may be unbridled cell growth, or cancer.
The first generation pups born to these mice contained no telomerase and very long telomeres. These mice all developed lymphomas by the time they were 7 months old. The researchers then continued breeding the mice to see what would happen in later generations. By the fifth generation, the researchers discovered that the mice had short telomeres and stopped developing lymphomas.
When the researchers blocked the suicide machinery in these fifth-generation mice, they were very surprised to find that the mice still remained cancer free.
"We were confused as to what was going on; we thought for sure that blocking the cells, ability to commit suicide would lead to the cancer's returning," says Greider. A closer look showed microtumors in the mice's lymph nodes that had begun the road to cancer, but stopped, falling instead into a state of senescence.
"They don't die, they don't divide, they just sit there in permanent rest," says Greider. Greider, who won the Lasker Award in 2006 for her discovery of telomerase, says further study of the road to senescence should suggest new ways of preventing or treating cancer by interfering safely with telomerase and the cell-suicide system.
hopkinsmedicine
the after hours version of the Fbxl3 gene appears to interfere with normal regulation of the body clock on a cellular level. In mice and humans, there are molecular feedback loops that run over a period of roughly 24 hours to keep the body clock on time. A feedback loop is a cyclical system that relies on the input and breakdown of molecules to keep it running. One of the key components of this loop is a protein called Cry. We found that mice that carried the after hours gene also had a delayed Cry protein breakdown rate, leading to a slowdown in the molecular feedback loops and a lengthening of the body clock cycle.''Many questions remain as to how molecular feedback loops govern daily biological cycles. Exactly how and when Fbxl3 targets Cry for breakdown is the scientists next target. Dr Nolan commented:
We need to do a lot more research before this discovery could be applied to the human body clock cycle in any way, what it has shown us is yet another gene involved in controlling circadian rhythms and this in itself is a useful starting point for further study.''Original research paper: The After hours Mutant Reveals a Role for FBXL3 in Determining Mammalian Circadian Period is published in Science on 26 April.
mrc.ac/