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The human body has so many millions of cells that when things go awry in one, it's best to kill off the offender.
Changes in DNA that would lead to cancer if unchecked are common in the body, but when cells notice that their DNA is damaged, they will tidily commit suicide in the best interest of the organism.
A new study published in this month's edition of the journal Nature by Associate Professor of Medicine William G. Kaelin Jr. sheds new light on the contents of the cell's bottle of hemlock.
Scores of chemicals participate in the intricate web of interactions that control cell suicide. Fifty percent of all human cancers cause defects in one, the drably named p53. Without this protein, cells have trouble killing themselves to save the body from cancer.
Because of its key role, p53 has been a major subject of the search for a cancer cure. In 1997, immune system researchers at a French pharmaceutical company surprised the cancer research community with their serendipitous discovery of a close cousin of p53 which they named p73.
P73's pedigree suggests that it should be important in fighting cancer but it has proved surprisingly hard to pin down its function.
In some of the most interesting research on the subject, Kaelin showed a few years ago that p73 can be coaxed into involvement in cell suicide. In his latest paper he reports the surprising discovery that both p53 and p73 are activated by the same protein.
Lives of a Cell
The cell operates a number of checkpoints to make sure it is in good shape before it copies its DNA. Once it does so it has set in motion the process of dividing in two and cannot turn back.
It is these checkpoints that usually ensure that cells with damaged DNA don't divide. But cancerous cells try to skip over the safeguards and divide faster and more often than they should.
Dr. Phillip W. Hines, assistant professor of pathology, draws an analogy between cells and cars to explain how the cell tries to fight cancer. The disease tries to put the normal cell machinery on overdrive. The cell can respond by destroying itself or by putting on the breaks--stopping its movement through the cell cycle. Cancers try to disable p53 because it plays a key role in both of these cancer-fighting mechanisms.
"The ability to act as breaks and the ability to act as an executioner are probably functionally distinct jobs of p53, but both of them have the same result: stopping an aberrant cell from dividing," Hines says.
Welcome to the Family
Studies over the last three years have suggested that p73 is very different from its cousin. p53 is strongly expressed all over the body, but p73's expression is weak and variable. And p53 exists in only one form, but p73 seems to exist in several different forms.
Earlier this year Medical School Professor Frank McKeon genetically engineered mice that lack p73 to see whether they would develop cancer, just as mice that lack p53 do. The mice had "profound" defects in their metabolism and their nervous systems, but no tumors.
But other data suggests that the protein might be involved in cell death. Part of how p53 works is by attaching to different parts of the cell's DNA; in test tubes, p73 attaches to those same regions. It is located in a region of human chromosome 1 that is often damaged in cancer.
The Protein Was a Killer
The hunt was on to find the signals that normally operate to activate p73.
Kaelin's new experiments offer an intriguing preliminary answer; they show that a particular common protein spurs both p73 and p53 to do their jobs.
Taken together, Kaelin's results suggest that there are both usual and backup cell death pathways. p53 is a "professional tumor suppressor" and p73 is its understudy.
"Under normal conditions p73 is not a professional tumor suppressor," he said. "But if we are smart enough we might be able to make it act like one."
But even the basics of how p73 works are still unknown. What are the remaining proteins that talk with p73 to tell it to kill? How does it carry out its lethal program?
Medical School researchers are now doing experiments to try to answer these questions. And, with the recent identification of the protein that activates p73, they're already starting to dream about using the protein to help stop the progression of cancer.
Kaelin wants to try to coax cancerous cells to commit suicide by giving them very high levels of the molecule that turns on p53 and p73. No one had thought of doing this before because scientists thought that the cell suicide machinery was broken in cancers. But now it seems that there is an alternative cell suicide machinery that cancer overlooks.
"In your wildest dreams, one approach to treating cancer cells that lack p53 is to reawaken its cousin," Kaelin said.
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