Apoptosis

Edited by: Karen Young Kreeger M. Tewari, V.M. Dixit, "Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product," Journal of Biological Chemistry, 270:3255-60, 1995. (Cited in more than 130 publications as of February 1997) M. Tewari, L.T. Quan, K. O'Rourke, S. Desnoyers, Z. Zeng, D.R. Beidler, G.G. Poirier, G.S. Salvesen, V.M. Dixit, "Yama/CPP32ß, a mammalian homolog of CED-3, is a crmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase," Cell, 81:801-9, 1995. (Cited in more than 230 publications as of February 1997) Comments by Vishva M. Dixit, University of Michigan Medical School This pair of papers provides conclusive evidence for a group of proteins that are responsible for programmed cell death in mammals. The earlier paper, published in the Journal of Biological Chemistry (JBC), laid the groundwork for the later Cell paper. FINGERING THE CULPRIT: Studies by Muneesh Tewari, left, Vishva Dixit, and colleagues provided a definitive role for the ICE family of proteins in mammalian apoptosis. "The JBC paper was the first indication of the involvement of proteases in Fas and tumor necrosis factor [tnf]-induced cell death," says Vishva M. Dixit, a professor of pathology at the University of Michigan Medical School. "This was the first study that provided a definitive role for the ICE [interleukin-1b converting enzyme] family of proteins in these two types of apoptosis." ICE proteins have been previously implicated in mammalian apoptosis. The Fas antigen and tumor necrosis factor receptor are cytokine receptors that, by activating an apoptosis pathway, can eliminate virus-infected cells. The group inhibited cell death using the poxvirus crmA gene product, a viral inhibitor that is specific for ICE family members. "Here were cells that we exposed to tnf or Fas, and they were dead . . . within eight hours," remarks Dixit. "Then we put in crmA, and not only do the cells survive, but they multiply. "When Muneesh Tewari [the paper's first author and a graduate student in the Dixit lab] showed me that result, I knew we had taken a major step in figuring out the death pathway because we had completely disrupted the signal." Dixit says that the importance of the paper "has become more paramount because there were two papers that appeared about six months later in Nature" that reported similar results (M. Enari et al., Nature, 375:78-91, 1995; M. Los et al., Nature, 375:81-3, 1995). Dixit surmises that the three papers often get cited together. "The Cell paper is essentially an extrapolation of the work presented in the JBC paper because it says that clearly an ICE protease is involved in the pathway," he states. "The question that loomed large for the field was that there wasn't one mammalian ICE, but there are a number of ICEs that had been cloned. So the question was: Which of these was the mammalian deathase?" According to Dixit, the Cell paper suggests that its identity is actually a related ICE family member, much as was suggested by Yuri Lazebnik from Cold Spring Harbor Laboratory on Long Island, N.Y. (Y.A. Lazebnik et al., Nature, 371:346-7, 1994). The lab labeled this protease Yama, after the Hindu god of death. This enzyme turned out to be identical to CPP32b, the mammalian homolog of ced-3, a Caenorhabditis elegans apoptosis enzyme. "The importance of the Cell paper is that it was the first indication of a mammalian deathase, and suggests that it is the mammalian deathase that Yuri has been looking for," says Dixit. Late last year, Richard Flavell's group at Yale University knocked out CPP32ß and showed definitively that this enzyme is involved in mammalian apoptosis (K. Kuida et al., Nature, 384:368-72, 1996). All of this work "fingered one of the ICE family members as the most likely mammalian deathase," explains Dixit. A group at Whitehouse Station, N.J.-based Merck and Co. Inc. came to the same conclusion in a paper in Nature four weeks later than the Dixit lab's paper on Yama (D.W. Nicholson et al., Nature, 376:37-43, 1995). "Right now we're looking for what appears to be the missing link in the death story," relates Dixit. "This missing link is ced-4, one of the three genes found in C. elegans to be involved in cell death. Although ced-4 has been cloned, nothing is known about how it induces cell death."

Apoptosis

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