Death Proteins Required for T-cell Maturation Promote Cell Proliferation and Mitochondrial ROS Production

AbstractResearchers at the University of Pennsylvania School of Medicine have found that proteins known to promote cell death are also necessary for the maturation and proliferation of immune cells.The Penn scientists discovered that in the cells that lack the pro-death proteins Bax and Bak, calcium signaling is disrupted and energy production is reduced. Restoration of Bax corrects the signaling problems, increases energy production, and stimulates cell division.The findings bolster the team’s hypothesis that metabolic cell activity directly controls life and death decisions in cells.The results were published online in the journal Immunity.Researchers at the University of Pennsylvania School of Medicine have found that proteins known to promote cell death are also necessary for the maturation and proliferation of immune cells. Activation of T-cell receptors on the surface of lymphocytes by foreign antigens initiate a calcium-mediated signaling pathway that ends in cell differentiation and growth. The Penn scientists discovered that in the cells that lack the pro-death proteins Bax and Bak, calcium signaling is disrupted and energy production is reduced. Restoration of Bax corrects the signaling problems, increases energy production, and stimulates cell division.The results, published online in the journal Immunity, bolster the team’s hypothesis that metabolic cell activity directly controls life and death decisions in cells. This issue also includes a related commentary by the study’s lead author, Russell Jones, PhD, and senior author Craig B. Thompson, MD.It is well known that cells that lack Bax (Bcl-2-associated X protein) and Bak (Bcl-2-antagonist/killer) continue living under conditions that would cause normal cells to undergo programmed cell death or apoptosis. What is less well understood, is why lymphocytes missing these key proteins are unable to trigger a strong immune response and do not proliferate as normal in response to stimulation.“We simply say they are the same thing,” says Thompson, Director of the Abramson Cancer Center and Chairman and Professor of Cancer Biology and Medicine. “The molecular basis of both findings is based on how Bax and Bak work on intracellular membranes.”Specifically, the team found that when the T-cell receptor was stimulated on mutant cells lacking both proteins, proliferation was severely reduced relative to normal cells. Closer investigation showed that the amount and rate of calcium release from intracellular stores was altered in the mutant cells.The inadequate calcium signals were unable to stimulate the mitochondria, which are the energy factories in the cell. Without mitochondrial activation, a key by-product of energy production, called reactive oxygen species or ROS, were not produced. And because ROS tell the cell to divide, cell proliferation is compromised.Although Thompson’s group investigated the function of Bax and Bak in T cells, the team thinks their findings will likely apply to many different cell types. When a cell receives signals to increase metabolism, it increases mitochondrial activity and energy production. That leads to the production of more energy than the cell can deal with, and consequently, the release of ROS. “It is the release of reactive oxygen species by the mitochondria that actually generate the proliferation. We think that is the basis of all cell proliferation,” says Thompson.The study was funded by the National Institutes of Health and the Abramson Family Cancer Research Institute. Russell Jones received support from the Cancer Research Institute and the Canadian Institutes for Health Research. Co-author Connie Krawczyk received support from the Human Frontiers Science Program.Additional co-authors include Thi Bui, Carl White, Muniswamy Madesh, Connie Krawczyk, Tullia Lindsten, Brian Hawkins, Sara Kubek, Hao Shen, and J. Kevin Foskett from Penn; Kenneth Frauwirth from the University of Maryland; Y. Lynn Wang from the Weill Medical College of Cornell University; Stuart J. Conway, H. Llewelyn Roderick, and Martin D. Bootman from The Babraham Institute.###The Abramson Cancer Center (ACC) of the University of Pennsylvania is a national leader in cancer research, patient care, and education. The pre-eminent position of the Cancer Center is reflected in its continuous designation as a Comprehensive Cancer Center by the National Cancer Institute for 30 years, one of 39 such Centers in the United States. The ACC is dedicated to innovative and compassionate cancer care. The clinical program, comprised of a dedicated staff of physicians, nurse practitioners, nurses, social workers, physical therapists, nutritionists and patient support specialists, currently sees over 50,000 outpatient visits, 3400 inpatient admissions, and provides over 25,000 chemotherapy treatments, and more than 65,000 radiation treatments annually. Not only is the ACC dedicated to providing state-of-the-art cancer care, the latest forms of cancer prevention, diagnosis, and treatment are available to our patients through clinical themes that developed in the relentless pursuit to eliminate the pain and suffering from cancer. In addition, the ACC is home to the 300 research scientists who work relentlessly to determine the pathogenesis of cancer. Together, the faculty is committed to improving the prevention, diagnosis and treatment of cancer.PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.Penn's School of Medicine is currently ranked #3 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.The University of Pennsylvania Health System includes three hospitals — its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center — a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

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