Meeting report: mechanisms of cell death 2000.

Abstract

“Truth does not become more true by virtue of the fact that the entire world agrees with it, nor less so even if the whole world disagrees with it” (Maimonides). This quotation best expresses the theme of the third biennial meeting of the International Cell Death Society held on May 6, 2000 in Escorial, Spain. The meeting entitled “Mechanisms of Cell Death,” organized by Zahra Zakeri, Richard A. Lockshin, and Carlos Martinez-A. It filled to capacity with over 300 participants. The speakers included both junior (55%) and senior (45%) scientists with 42% women. The broad perspective covered six sections: Development and Aging; Extracellular Signaling; Cell Death in Disease; Cellular Signaling; Cell Survival; and Proteolysis, ending with a workshop on phagocytosis. In this meeting many of the speakers either challenged ideas that recently dominated the field, or elaborated and nuanced ideas that previously were considered to be straightforward. For instance, initiation of cell death remains as complex a question as ever. Numerous promoter sites for the Drosophila gene reaper indicate very complex regulation (Abrams). In AIDS, there is a complex balance between host-driven pro-apoptotic and virus-driven antiapoptotic forces (Cossarizza) and a dysregulation of cytokines (Gougeon). The role of mitochondria in apoptosis was addressed at several levels. Kroemer demonstrated that Bcl2 could inhibit a liposome-embedded Permeability Transition Pore Complex. Martinou considered that Bax can release cytochrome c but also can act by a secondary mechanism. It was reported that at the cellular level Bcl2 and bax differed in their capacities to localize to different compartments, indicating that their behavior and hence functions in intact cells may differ from strictly biochemical measurements in vitro (Borner). Physical, autophagic, loss of mitochondria was argued by Tolkovsky as a death commitment point. Depolarization of only a subset of mitochondria could initiate the apoptotic program. (D’Herde). An intriguing change of view was reflected in the mode of activation and function of the caspases, and the relationship of caspase-dependent to caspase-independent death. Several researchers suggested functions other than apoptosis for caspases. Hardwick found that proteolysis converted anti-apoptotic proteins into pro-apoptotic proteins, thus guaranteeing the launching of apoptosis. Roy contended that the dormancy of caspases is controlled by a DDD (Asp-Asp-Asp) “safety catch” sequence in caspases. Caspase 8 was shown to correlate inversely with tumor radiosensitivity (Zhivotovsky). FLIP inhibits casp8 (Thome) and HSP72 blocks casp3 activation (Anderson). Jaatella reported the intriguing finding that depletion of HSP70 (by antisense mRNA) activated a tumor-specific death program that was independent of caspases and bypassed bcl-2. Evidence was presented for the function of caspases in roles other than in cell death. Apaf1 and caspase 9 are important in tumor development (Soengas). Woo, looking at casp3 knockouts, demonstrated a role for casp3 in proliferation, perhaps by downregulating p21. Silke, using a novel screen in yeast, found that XIAPs inhibit UV-induced apoptosis, a surprising finding because they were supposed to act at a far downstream point. Other proteases such as matrix metaloproteinases and stromelysin were posited to be an extremely important part of autophagic death in tadpole metamorphosis (Shi; also noted by Linden) and granzyme B can produce reactive oxygen substances and ψm without the participation of caspases (Greenberg). More evidence for the involvement of other proteases was presented by Torriglia, who showed that, in lens, cleavage of leukocyte elastase inhibitor (LEI) achieved a double purpose: it relieved inhibition of a serine protease; and it turned LEI into L-DNase II, which is involved in degradation of the DNA. Roberg found that, in oxidative stress-induced apoptosis, lysosomal destabilization preceded mitochondrial changes, and pepstatin, an inhibitor of cathepsin D, blocked progress of apoptosis. Bursch, arguing that autophagic death differed from chemical apoptosis, emphasized that autophagic death requires ATP, is specific for elimination of different types of organelles, and requires extensive involvement of the cytoskeleton. The meeting was one of the first to emphasize phagocytosis, both in the primary meeting and in the following