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The protein p53, naturally occurring in all cells, is a powerful cancer fighter, but it kills normal as well as cancerous cells if it stays active in the nucleus for too long. Now Columbia University Medical Center research shows that cells usually get rid of the danger by quickly exporting the molecules out of the nucleus after they have done their job, instead of destroying the molecules as previously believed. The findings provide more details of how p53, the "guardian of the genome," could be manipulated in tumors to improve cancer therapeutics. The study was published in the Dec. 12 issue of Science.

The p53 protein receives countless signals about cell activity and if a cell is damaged will either initiate repair of a cell's damaged DNA or start apoptosis, the cell's suicide plan. If p53 initiates repair, it must be quickly subdued after the repairs are complete to prevent cell death. An enzyme, Mdm2, usually inactivates p53 by adding ubiquitin molecules to it. A chain of four or more ubiquitins usually tells the cell to destroy the protein.

But trying to glean more detail about Mdm2 was confusing. In one hypothesis, Mdm2 also helps ship p53 into the cytoplasm, where p53 is destroyed. In the other hypothesis, Mdm2 has no other role and p53 degrades right in the nucleus.

Researchers in the Institute for Cancer Genetics have now found that Mdm2 does both, depending on its concentration. When levels of Mdm2 are high, Mdm2 adds a chain of ubiquitins to p53 and p53 is degraded inside the nucleus.

But when Mdm2 levels are low, the molecule acts differently and only tags p53 with a single ubiquitin. The single ubiquitin then acts as a shipping signal, something never seen before in the nucleus. The p53 molecule with single ubiquitins are shipped from the nucleus, where they can potentially do damage, into the cytoplasm where they're inactive. Because Mdm2 levels are usually low, exporting is the more prevalent mechanism.

Exporting p53 is more common because it is cheaper and faster than degradation, says the study's senior author Dr. Wei Gu, assistant professor of pathology. "Adding four or more ubiquitins to p53 so that it can be degraded is very time- and energy-consuming. But adding just one is very fast and economical," Dr. Gu says. "Also if the mono-ubiquinated p53 is kept in the cytoplasm, the cell may be able to quickly send it back into the nucleus if it's needed again."

For cancer researchers, whose goal is to keep p53 active in malignant cells, the finding shows preventing degradation is not the only way to keep p53 working. Inhibiting exportation may work just as well.

For other researchers, the work may represent a turning point. "People usually think of ubiquitin for protein degradation," Dr. Gu says. "Our finding that it's used as a signal changes the view about ubiquitin. With p53, and potentially other proteins, it is used for moving molecules around the cell."

The research was supported by the Avon Foundation, the Irma T. Hirschl Trust, and the National Cancer Institute. Dr. Gu is a Leukemia & Lymphoma Society Scholar.

–Susan Conova

Columbia University Medical Center researchers have found that stroke puts a person at higher risk of developing Alzheimer's disease. Alzheimer's disease and stroke are common afflictions of the elderly, but the relationship between the two has been unclear.

"We found that the people who developed clinical Alzheimer's disease during the course of the study were about 60 percent more likely to have had a stroke," says Dr. Lawrence S. Honig, first author of the study and associate professor of clinical neurology. This increased risk of Alzheimer's was even greater in persons who had a stroke and cerebrovascular disease risk factors such as diabetes, high blood pressure, or heart disease.

"It appears that the added injury to the brain from stroke may cause people to develop symptoms of Alzheimer's earlier than they might have otherwise," Dr. Honig says. "Our findings suggest more attention should be paid to cerebrovascular risk factors to prevent strokes, as a stroke may increase the chance of developing symptoms of Alzheimer's disease."

The findings are based on an eight-year study of 1,766 Medicare recipients age 65 and older in northern Manhattan, which included Hispanics, African-Americans, and whites. Dr. Richard Mayeux, Gertrude H. Sergievsky Professor of Neurology, Psychiatry, and Epidemiology, is principal investigator of the study and senior author of the paper, published in the December issue of the Archives of Neurology.

It remains unclear how stroke contributes to the risk of developing Alzheimer's disease. The researchers plan to examine postmortem brain tissue in research subjects. They will look at the relationship between actual brain tissue lesions from stroke and Alzheimer's disease pathological findings (plaques and tangles) to see if they can further clarify the relationship between the two conditions.

The view of stroke's link to Alzheimer's and, more generally, to dementia has evolved over time, Dr. Honig says. About 50 years ago, researchers felt dementia was caused by stroke. Then, as investigators conducted more brain autopsy studies, they realized Alzheimer's disease caused most dementia and that stroke was not that significant a contributor. Now the view is more inclusive — even though Alzheimer's may be the principal cause for dementia, stroke is still relevant.

The study was supported by grants from the National Institutes of Health, the Charles S. Robertson Memorial Gift for Alzheimer's Disease Research from the Banbury Fund, and the Blanchette Hooker Rockefeller Foundation.

–Matthew Dougherty


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