APOPTOSIS

David Baltimore A.A. Beg, D. Baltimore, "An essential role for NF-kappa B in preventing TNF-alpha -induced cell death," Science, 274:782-4, 1996. (Cited in more than 300 papers since publication.) Comments by David Baltimore, a professor of biology and president of the California Institute of Technology Apoptosis. Programmed cell death. Several proteins carry a signal that commands cells to commit suicide for the greater good of the organism. But if these portable time bombs are circulating around the bloodstream, what protects all of the normally functioning cells from destruction? One explanation is that protective mechanisms prevent cells from following the apoptosis order. In fact, this study suggests that TNF-alpha --a powerful cell death signal--sends two simultaneous signals: one an instruction to commit suicide, and the other activating a cellular protein complex--called NF-kappa B--that prevents cellular suicide. NF-kappa B--made up of two independent proteins called p50 and p65--was first uncovered in the 1980s as researchers looked for proteins that influence expression of immunoglobulin light chains. Their interest intensified when they discovered that NF-kappa B is present in almost all cells, but it usually is bound to an inhibitor that keeps it inactivated. When the complex is disrupted, NF-kappa B drifts to the nucleus to initiate transcription of genes that prevent cell death. "It was probably the first well-worked-out system for activation of a transcription factor," explains David Baltimore, a professor of biology and president of the California Institute of Technology, and the lead author of this paper. It also became clear that NF-kappa B influences many other genes besides immunoglobulin light chains, including some involved in inflammatory and immune responses. To study the molecule's effects, Baltimore's team created NF-kappa B-knockout mice, but mice deficient in p65 were not born. His co-author, Amer Beg, an assistant professor of biological sciences at Columbia University, traced the problem back to liver cells that suffered a mass cell death during development. They turned instead to embryonic fibroblasts derived from the knockout embryos and studied their response to compounds that induce NF-kappa B, including TNF-alpha. Sure enough, several proteins were not produced in the p65-knockout cell line, demonstrating "precise control of synthesis by p65," says Baltimore. And there it might have ended, except that Beg noticed that the cells began dying after about 10 hours, while the wild-type cells remained alive. "Amer had the wit to realize that this was a potentially important observation, because it could mean that one of p65's roles was natural protection against cell death," says Baltimore. That suspicion was soon verified, as the knockout cells were "rescued" by transfecting them with a separate vector to produce p65. Using different techniques, two other groups came to the same conclusion at about the same time, and all three papers were published simultaneously in the same issue of Science1. Baltimore's paper has slightly more citations than the others possibly because the knockout-mouse model is "particularly unambiguous," says Baltimore, while methods used in the other papers gave results more open to interpretation. "We now recognize that when receptors activate cell-death pathways, they often also activate anti-cell-death pathways, and which pathway dominates depends on factors we don't understand very well," notes Baltimore. "How that balance [of competing pathways] is achieved is a major topic of research." D.J. VanAntwerp, S.J. Martin, T. Kafri, D.R. Green, I.M. Verma, "Suppression of TNF-alpha -induced apoptosis by NF-kappa B," Science, 274:787-9, 1996 (cited in more than 270 papers); C.Y. Wang, M.W. Mayo, A.S. Baldwin, "TNF- and cancer therapy-induced apoptosis: Potentiation by inhibition of NF-kappa B," Science, 274:784-7, 1996 (Cited in more than 285 papers).

APOPTOSIS

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