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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.

The chemical heme is essential for most forms of life. It exists in hemoglobin for oxygen transport, in cytochromes for cellular energy production, and in guanylate cyclase for blood pressure regulation. The molecule itself is tiny, a flat snowflake of a carbon framework surrounding a single atom of iron, but it is crucial for the cellular process of respiration and the action of nitroglycerine.

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.     

Meanwhile, according to Dr. Tang and his colleagues, there is already a known agent that can relieve Maxi-K from heme inhibition. NS1619 is known as the "Maxi-K opener," and, as the researchers have shown, readily reverses the heme-mediated inhibition.

Breast Cancer Susceptibility Genes and DNA Repair

A study led by scientists at The Wistar Institute defines a functional role for the tumor suppressor proteins BRCA1 and BRCA2 in breast cancer. The findings, presented in the November issue of the journal Molecular Cell, also identify a number of novel proteins that work alongside BRCA1 and BRCA2 and might also play a part in breast cancer. These proteins offer an important set of new targets for possible anti-cancer drugs.

The link between the BRCA1 and BRCA2 genes and hereditary breast cancer was first identified in the early 1990s, but the biological function of the BRCA1 and BRCA2 proteins had remained elusive. The Wistar researchers demonstrated how the two proteins combine with others to form a complex called BRCC (BRCA1-and BRCA2-containing complex) and defined the role of the complex in regulating DNA repair. The researchers also discovered two new proteins that are part of BRCC and linked one of them, BRCC36, to sporadic breast cancers.

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.

Following treatment of cells with DNA-damaging radiation, BRCC interacted with p53 and, to a lesser degree, a known DNA repair enzyme. According to the Wistar researchers, this suggests that BRCC does not directly repair DNA. Instead, BRCC appears to regulate the proteins that cause the cell to divide and influence the proteins that repair DNA.

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

In a new research study, two prototype oral vaccines have both been shown capable of inducing protection against a dangerous virus in newborn mice. If the new vaccines are able to do the same for human newborns, they might be able to address an important window of immunological vulnerability in the lives of infant children. Particularly in the developing world, where the threat of infectious diseases is generally greater than in the developed world, many lives might be saved with vaccines of this type.

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.

The potential significance of the new study lies in the effectiveness of the prototype vaccines in newborns. Although newborns are protected from most common viral infections immediately after birth by antibodies received from their mothers, these antibodies decline in the first weeks and months of life as the fledgling immune system grows in its capacity to generate its own antibody protections against viruses. Between the waning of maternal-antibody protection and the development of a fully functional immune system in the infant, a period of relatively poor defense against disease for infants is frequently seen. This is partly because the infant immune system is not yet sufficiently developed, but also because the maternal antibodies, while protecting the infant from infections, can interfere with the efficacy of traditional vaccines.

"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."



  Almanac, Vol. 50, No. 14, November 25, 2003