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Molecule that Makes Life Possible

Heme, the iron-bearing, oxygen-carrying core of hemoglobin, makes it possible for blood to carry oxygen, but researchers from Penn's School of Medicine have determined how free-floating heme can also make traumatic events worse by damaging tissue. The researchers presented their findings in the October 2 issue of the journal Nature. Fortunately, the researchers also identified a chemical that can be targeted by drug developers to impede the deleterious effects of free-floating heme.

Following a traumatic event--such as an accident, a stroke, a heart attack or even surgery--heme floods the spaces between and inside cells and exacerbates the damage. It does so by shutting down an important cell membrane channel, an action that kills neurons and constricts blood vessels. While investigating this process, the researchers also determined that a chemical called NS1619 restores the function of the cell membrane channel. NS1619 and its derivatives could be the source for a new drug--one that prevents the secondary events that worsen trauma damage.

"Normally, cells can compensate and recycle loose heme. But when larger concentrations are released, heme can gum up the works, specifically the Maxi-K ion channel, a cell membrane protein important for blood vessel relaxation and neuron excitability," said Dr. Xiang Dong Tang, staff scientist in the department of physiology.

Maxi-K is a channel that moves potassium ions out of cells. In the Nature paper, Dr. Tang and his colleagues prove that the Maxi-K protein possesses sites that bind heme. If these sites were removed or altered, heme could not effect Maxi-K proteins.


Studying the heme recycling system might prove useful in developing treatments for preventing the secondary damage set off by heme. Certain cells, such as neurons, do have ways of transporting heme. If the "heme transport" is identified and the specific blocker is found, it could help prevent symptoms resulting from trauma and bleeding.     


Breast Cancer Susceptibility Genes and DNA Repair



Dr. Shiekhattar, an associate professor at the Wistar Institute and senior author on the study, and his colleagues determined that the BRCC protein complex acts as one large regulatory enzyme. They discovered that one target of BRCC is a protein familiar to cancer researchers called p53, a potential cancer-promoter if left unregulated. BRCC attaches a chemical tag, a ubiquitin group, p53. The ubiquitin tag signals the cell's digestive machinery to destroy the marked protein.


To study how BRCA1 functioned in the cell, Dr. Shiekhattar and his colleagues created a line of cells that produce a specially tagged version of BARD1--a protein known to interact with BRCA1. The tag allowed Dr. Shiekhattar to isolate BARD1 and any protein found with it. When they found the tag attached to a large complex of proteins, mass spectrometric sequencing allowed them to determine and isolate the individual parts of the complex.

Among the proteins caught in this molecular dragnet, were BRCA2--indicating that BRCA2 worked directly with BRCA1 in cells--and two new BRCC subunits. Dr. Shiekhattar and his colleagues learned that disrupting the function of the new subunits, named BRCC36 and BRCC45, made cells more susceptible to DNA damage from ionizing radiation and interfered with the ability of BRCC to halt the cell cycle at the checkpoint before cell division.

Sirtuins in Metabolism, Aging, Gene Expression

In recent years, scientists have learned that members of a family of enzymes known as sirtuins play critical roles in a wide array of vital life processes, including metabolism, aging, and gene expression. Some studies have shown that low-calorie diets that extend life also boost sirtuin activity dramatically, suggesting an intriguing link between metabolism and aging through sirtuins. And in September, a team of investigators found that a sirtuin-activating compound found in red wine increased the life span of yeast cells by more than two-thirds.

Humans have at least seven different sirtuins performing different tasks, and given the evident importance of the work they do, researchers have been trying to better understand how they function. Insights into their mode of action could represent early steps toward developing a novel class of drugs that might promote health in various ways.

Now, structural biologists at The Wistar Institute studying the role of sirtuins in gene expression--specifically in turning genes off--report new findings that significantly illuminate how sirtuins work. The results point to a mechanism of action likely to be general for the entire sirtuin enzyme family and may offer the beginnings of an explanation for how metabolism and aging may be linked through the mechanisms that control gene expression. The research is featured on the cover of the November issue of the journal Structure.

Using X-ray crystallography and other techniques of structural biology, Dr. Ronen Marmorstein, a professor in the Gene Expression and Regulation Program and senior author on the Structure study and his group detailed the structure of a sirtuin from yeast while bound to two molecules associated with its biological function. One part of the sirtuin was bound to a derivative of a molecule called NAD, which has a pivotal responsibility in metabolism--it's needed to break down glucose. The other part of the sirtuin was bound to a specific site on a histone protein. Histones are primary players in controlling genes, and in this case the sirtuin Sir2 is the site of action for silencing gene expression.

Vaccines to Protect Newborns in Developing World


The vaccines are based on human and chimpanzee adenoviruses that have been altered in the laboratory so that they are unable to replicate. In the current proof-of-principle study the viruses were engineered to incorporate a gene from the rabies virus. Following oral administration of the vaccine, newborn mice developed antibodies that protected them from subsequent exposure to the rabies virus. By extension, the researchers say, the same vaccine strategy might also prove effective against other viral diseases, such as measles, viral respiratory infections, and viral diarrhea. A report on the study findings appeared in the October 15 issue of the Journal of Immunology.


"These new vaccines we've developed trigger the production of protective antibodies in newborn mice during a time in their lives when traditional vaccines are commonly less than effective," said Dr. Hildegund C. J. Ertl, professor and head of the Immunology Program at Wistar and senior author of the study. "This had potentially important public-health implications, especially in the developing world. In addition, there are oral vaccines, which could make them easier to distribute and administer in those same areas."


