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Third Public Conference: Cellular Aging
and Apoptosis Regulation of the Oxidative Stress
Response and Life Span by the Mammalian Shc Gene Speaker Several gene mutations in invertebrates have been shown to extend life and enhance resistance to stresses such as ultraviolet light or reactive oxygen species. But no stress-regulating genes had been identified in mammals until Dr. Pelicci and his coworkers showed that targeted mutations of the p66shc gene had these effects in mice. Dr. Pelicci chairs the Department of Experimental Oncology at the European Institute of Oncology, Milan, and is also an Associate Professor of Oncology at the University of Parma. He received his M.D. and Ph.D. from the University of Perugia and held postdoctoral fellowships at Istituto di Clinica Medica I, Institut National de la Sante et de la Recherche Medicale, and New York University Medical Center. In addition to receiving numerous awards, Dr. Pelicci serves on the editorial boards of journals published in Italy and the United States. Topic One of the first clues about the regulation of mammalian stress response emerged from Dr. Pelicci's laboratory, when he and his coworkers reported that targeted mutation of the mouse p66shc gene bolstered stress resistance and prolonged life. They view the p66shc protein, like other shc adaptor proteins, as one step along a signal transduction pathway that couples an activated tyrosine kinase receptor to Ras. The normal function of p66shc appears to be inducing apoptosis in cells undergoing oxidative stress. When Dr. Pelicci's team knocked out the p66shc gene in mice, fibroblasts from those animals exhibited increased resistance to oxidative and ultraviolet light damage. The animals themselves lived about one-third longer than normal mice, even though their calorie intake was not restricted. The researchers hypothesize that p66shc, which is concentrated in mitochondria, interferes with the metabolism of reactive oxygen species, allowing them to accumulate and trigger apoptosis. Thus, when the gene has been deleted, apoptosis is delayed or blocked. The researchers wondered whether the price for living longer would
be a greater susceptibility to tumors. But when they compared mice that
were hetero- or homozygous for the p66shc deletion with control
animals, they saw no increase in spontaneous or induced tumors in mice
with the deletion. Future studies will home in on the exact role of
p66shc in mitochondrial function.
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