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RESEARCH BRIEFS Structure Solved For Cell Death ProteinA paper in the March 5 Cell affords scientists an intimate look at a recently discovered programmed cell death--or apoptosis--protein, BID. Using nuclear magnetic resonance technology, researchers led by Gerhard Wagner, the Elkan Blout professor of biological chemistry and molecular pharmacology, have determined its atomic structure. The study is a collaboration with Junying Yuan, associate professor of cell biology, whose group reported last year that BID connects a well-understood molecular-death pathway to the mitochondria. Current apoptosis research tries to understand how the mitochondria sustain damage after death-inducing signals have penetrated the cell. BID is a major suspect. Mitochondrial damage can seal the cell's fate by activating caspases, the death enzymes.
Wagner and graduate student James Chou were surprised to see that the structure of BID greatly resembled a protein it binds to, the death-inhibitor Bcl-xL, even though the sequences of the two proteins are barely related. Using data from another study, the scientists modeled the binding of BID and Bcl-xL (see image). They describe how a biochemical change that activates BID as the cell staggers towards death helps it bind Bcl-xL more readily. This wrests Bcl-xL away from its usual binding partner, another cell death regulator, APAF-1, helping to unleash a fatal caspase chain reaction. BID has another trick up its sleeve, the scientists report. Its structure resembles that of bacterial toxins that bore holes in cell membranes, suggesting it might insert itself into the mitochondrial membrane and disturb its electric balance. The latest in a series of studies revealing the structures of cell death molecules, this work broadens a perplexing observation in the field. Cell death proteins that are only distantly related by sequence closely resemble each other in structure yet can have opposing ultimate effects in the cell. Future work will aim at sorting out the molecular mechanisms at work, the authors note. Low Birthweight Linked To Type II DiabetesA relationship between low birthweight and the incidence of adult conditions like hypertension and cardiovascular disease is well established. Research also correlates low birthweight and Type II diabetes, but many of these studies have not included sufficient numbers of participants to prove the association. And in the analysis of their data, some have failed to take into account potential explanatory factors like history of paternal or maternal diabetes, body mass index, and cigarette smoking. In an effort to clarify the link between low birthweight and the risk of diabetes, Janet Rich-Edwards, HMS instructor in ambulatory care and prevention at Harvard Pilgrim Health Care, and Joann Manson, HMS associate professor of medicine at Brigham and Women's Hospital, and colleagues from these institutions looked at the birthweight and incidence of Type II diabetes in a cohort of 69,526 women. As published in the Feb. 16 Annals of Internal Medicine, after adjusting for potentially confounding variables, the authors found that low birthweight is indeed associated with increased risk for Type II diabetes. This inverse relationship was strongest among women whose mothers had no prior history of diabetes. The findings do not indicate that low birthweight causes Type II diabetes, the authors stress. Rather, their analysis might hint at factors that affect prenatal growth and influence the future risk of developing Type II diabetes. According to Manson and colleagues, their study provides grounds to examine the diet and hormone levels of pregnant women and how these relate to glucose tolerance in their children, data that may shed light on the link between birthweight and Type II diabetes. --This and following briefs by Sylvia Pagán Westphal Mouse Model of Cushing's Disease DevelopedCushing's disease, described decades ago by Harvard neurosurgeon Harvey W. Cushing, is an endocrine disorder caused by pituitary overproduction of adrenocorticotropic hormone (ACTH). Patients with Cushing's have increased ACTH that leads to high levels of the stress hormone cortisol, and exhibit hallmark symptoms such as skin that bruises easily, blood sugar and blood pressure abnormalities, and abnormal fat deposition around the neck, known as a "buffalo hump." MDPhD student Christoph Westphal, Philip Leder, the John Emory Andrus professor of genetics, and colleagues report in the March 5 Cell that mice lacking a gene called neuroendocrine 7B2 not only have the characteristic buffalo hump, but suffer from a range of symptoms that affect people with Cushing's disease. Neuroendocrine 7B2 had been previously linked to the processing of peptide hormones and was thought to exert its effect by facilitating the functioning of a protein called prohormone convertase 2 (PC2). To test this hypothesis, Leder and his colleagues employed a novel transposon-based technique to create mice lacking functional 7B2. The authors saw that PC2 was no longer active in the 7B2 knockout mice, thus confirming the link of 7B2 to PC2 function. However, they were surprised to find that their mice were much sicker than previously studied mice lacking PC2, and it was the characteristic buffalo hump that suggested the rodents could have Cushing's disease. According to the authors, the mice will increase understanding of Cushing's disease and pituitary hormone processing. Species-Jumping DNA May Aid Bacteria StudiesNomads of the genome, transposons are mobile elements that can jump in and out of the DNA in a wide variety of organisms. In most cases, however, transposons are highly specific to a particular species, and do not "jump," or transpose, unless they are in a cell of their endogenous host. An exception to this rule are the transposons of the mariner super family, which have been found in the genomes of diverse eukaryotic organisms and can transpose in distantly related insects and even vertebrate cells, reflecting a remarkable lack of host specificity. Yet in the world of bacterial research, only host-specific transposons have been available to scientists. The ones used in gram-positive bacteria did not work in their gram-negative cousins. Coming to the rescue are four HMS faculty members: Eric J. Rubin, instructor in medicine at Massachusetts General; Brian Akerley, research fellow in microbiology and molecular genetics; John Mekalanos, the Adele Lehman professor of microbiology and molecular genetics; and Robert Husson, assistant professor of pediatrics at Children's. They report in the Feb. 16 PNAS that a mariner transposon from a horn fly is capable of transposing across species boundaries. The authors show that this eukaryotic transposon works equally well in the gram-negative bacterium E. coli and in gram-positive mycobacteria. Transposition seems to occur randomly in bacteria, and the only sequence requirement is that the nucleotides thymine and adenine must be next to each other. The authors speculate that this mariner-based system will be active in many other bacterial strains and that these transposons will therefore provide a universal tool to study many organisms--including pathogens--where properly developed genetic systems were, until now, lacking. Pulse Pressure Predicts Congestive HeartFailure in Elderly Congestive heart failure (CHF), a significant cause of morbidity and mortality in the U.S., is the leading hospital diagnosis for people older than 65. Although it is known that high blood pressure is a risk factor for CHF, other risk factors have not been conclusively identified, especially in the elderly population. Now an article in the Feb. 17 JAMA provides evidence that arterial stiffness, the loss in aortic elastic capacity that comes with age, is a risk factor for CHF in the elderly. The study was done by Claudia Chae, HMS instructor in medicine at Massachusetts General, and colleagues at Brigham and Women's, the Harvard School of Public Health, and the East Boston Neighborhood Health Center. The authors selected participants in the East Boston Senior Health Project who had complete blood pressure measurements and no prior diagnosis of CHF. They measured pulse pressure, an index of arterial stiffening, and followed these 1,621 individuals for an average of 3.8 years. After controlling for variables including age, sex, history of diabetes mellitus, coronary heart disease, and other conditions, the researchers found that pulse pressure was independently and linearly associated with risk of CHF. In fact, every 10-mm Hg rise in pulse pressure was associated with a 14 percent increase in the risk of CHF. Based on these results, the authors suggest that pulse pressure should be a useful tool to identify elderly patients at risk for CHF. |
