[Abstract unavailable

Death receptors have been recently identified as a subgroup of the TNF-receptor superfamily with a predominant function in induction of apoptosis. The receptors are characterized by an intracellular region, called the death domain, which is required for the transmission of the cytotoxic signal. Currently, five different such death receptors are known including tumor necrosis factor (TNF) receptor-1, CD95 (Fas/ APO-1), TNF-receptor-related apoptosis-mediated protein (TRAMP) and TNF-related apoptosis-inducing ligand (TRAIL) receptor-1 and -2. The signaling pathways by which these receptors induce apoptosis are rather similar. Ligand binding induces receptor oligomerization, followed by the recruitment of an adaptor protein to the death domain through homophilic interaction. The adaptor protein then binds a proximal caspase, thereby connecting receptor signaling to the apoptotic effector machinery. In addition, further pathways have been linked to death receptor-mediated apoptosis, such as sphingomyelinases, JNK kinases and oxidative stress. These pro-apoptotic signals are counteracted by several mechanisms which inhibit apoptosis at different levels. This review summarizes the current and rapidly expanding knowledge about the biological functions of death receptors and the mechanisms to trigger or to counteract cell death.Keywords : apoptosis; Bcl-2; caspase; CD95 (APO-1/Fas) ; death receptor; inhibitor of apoptosis protein; nuclear factor-κB ; tumor-necrosis factor; tumor-necrosis-factor-related apoptosis-inducing ligand; tumornecrosis-factor-receptor-related apoptosis-mediating protein.Apoptosis or programmed cell death is the innate mechanism modelling, immune regulation and tumor regression. Cells undergoing apoptosis show a sequence of cardinal morphological by which the organism eliminates unwanted cells. In contrast to necrosis, apoptosis is the most common physiological form of features including membrane blebbing, cellular shrinkage and condensation of chromatin. Biochemically, these alterations are cell death and occurs during embryonic development, tissue reassociated with the translocation of phosphatidylserine to the duced following traumatic injury or exposure to high concentra-

Autophagy and apoptosis are basic physiologic processes contributing to the maintenance of cellular homeostasis. Autophagy encompasses pathways that target long-lived cytosolic proteins and damaged organelles. It involves a sequential set of events including double membrane formation, elongation, vesicle maturation and finally delivery of the targeted materials to the lysosome. Apoptotic cell death is best described through its morphology. It is characterized by cell rounding, membrane blebbing, cytoskeletal collapse, cytoplasmic condensation, and fragmentation, nuclear pyknosis, chromatin condensation/fragmentation, and formation of membrane-enveloped apoptotic bodies, that are rapidly phagocytosed by macrophages or neighboring cells. Neurodegenerative disorders are becoming increasingly prevalent, especially in the Western societies, with larger percentage of members living to an older age. They have to be seen not only as a health problem, but since they are care-intensive, they also carry a significant economic burden. Deregulation of autophagy plays a pivotal role in the etiology and/or progress of many of these diseases. Herein, we briefly review the latest findings that indicate the involvement of autophagy in neurodegenerative diseases. We provide a brief introduction to autophagy and apoptosis pathways focusing on the role of mitochondria and lysosomes. We then briefly highlight pathophysiology of common neurodegenerative disorders like Alzheimer's diseases, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Then, we describe functions of autophagy and apoptosis in brain homeostasis, especially in the context of the aforementioned disorders. Finally, we discuss different ways that autophagy and apoptosis modulation may be employed for therapeutic intervention during the maintenance of neurodegenerative disorders.

The inactivation of programmed cell death has profound effects not only on the development but also on the overall integrity of multicellular organisms.

Mice lacking the gene encoding poly(ADP-ribosyl) transferase (PARP or ADPRT) display no phenotypic abnormalities, although aged mice are susceptible to epidermal hyperplasia and obesity in a mixed genetic background. Whereas embryonic fibroblasts lacking PARP exhibit normal DNA excision repair, they grow more slowly in vitro. Here we investigated the putative roles of PARP in cell proliferation, cell death, radiosensitivity, and DNA recombination, as well as chromosomal stability. We show that the proliferation deficiency in vitro and in vivo is most likely caused by a hypersensitive response to environmental stress. Although PARP is specifically cleaved during apoptosis, cells lacking this molecule apoptosed normally in response to treatment with anti-Fas, tumor neurosis factor ␣, ␥-irradiation, and dexamethasone, indicating that PARP is dispensable in apoptosis and that PARP−/− thymocytes are not hypersensitive to ionizing radiation. Furthermore, the capacity of mutant cells to carry out immunoglobulin class switching and V(D)J recombination is normal. Finally, primary PARP mutant fibroblasts and splenocytes exhibited an elevated frequency of spontaneous sister chromatid exchanges and elevated micronuclei formation after treatment with genotoxic agents, establishing an important role for PARP in the maintenance of genomic integrity.

BelgiumTHE Fas/ APO-l receptor is one of the major regulators of apoptosisl-7. We report here that Fas/ APO-l-mediated apoptosis requires the activation of a new class of cysteine proteases, including interleukin-lJl-converting enzyme (ICE)s--lo, which are homologous to the product of the Caenorhabditis elegans cell-death gene ced-3 (refs 11, 12). Triggering of Fas/ APO-l rapidly stimulated the proteolytic activity of ICE. Overexpression of ICE, achieved by electroporation and microinjection, strongly potentiated Fas/ APO-l-mediated cell death. In addition, inhibition of ICE activity by protease inhibitors, as well as by transient expression of the pox virus-derived serpin inhibitor, CrmA or an antisense ICE construct, substantially suppressed Fas/ APO-l-triggered cell death. We conclude that activation of ICE or an ICE-related protease is a critical event in Fas/ APO-l-mediated cell death.The signal transduction pathway elicited by Fas/ APO-l is almost completely unknown. Initiation of apoptosis may involve a new class of cysteine proteases, including the product of the C. elegans cell-death gene eed-3, mammalian interleukin-lfJ-converting enzyme (ICE) and the related proteases Nedd-2/Ich-l, prICE and CPP-32 (refs 11-17). Overexpression ofCED-3, ICE or Nedd-2/Ich-1 in Rat-l fibroblasts has been shown to result in apoptotic cell death 12.15. We therefore investigated whether Fas/ APO-I-mediated apoptosis involved an ICE-related proteolytic activity. In L929-APO-l cells 18 or B-lymphoblastoid SKW 6.4 cells, apoptosis triggered by the agonistic monoclonal antibody anti-APO-I was strongly inhibited by the ICE inhibitor YVAD-CHO, a tetrapeptide aldehyde (Ki = 0.76 nM)8 (Fig. la).

Death ligands not only induce apoptosis but can also trigger necrosis with distinct biochemical and morphological features. We recently showed that in L929 cells CD95 ligation induces apoptosis, whereas TNF elicits necrosis. Treatment with anti-CD95 resulted in typical apoptosis characterized by caspase activation and DNA fragmentation. These events were barely induced by TNF, although TNF triggered cell death to a similar extent as CD95. Surprisingly, whereas the caspase inhibitor zVAD prevented CD95-mediated apoptosis, it potentiated TNF-induced necrosis. Cotreatment with TNF and zVAD was characterized by ATP depletion and accelerated necrosis. To investigate the mechanisms underlying TNF-induced cell death and its potentiation by zVAD, we examined the role of poly(ADP-ribose)polymerase-1 (PARP-1). TNF but not CD95 mediated PARP activation, whereas a PARP inhibitor suppressed TNF-induced necrosis and the sensitizing effect of zVAD. In addition, fibroblasts expressing a noncleavable PARP-1 mutant were more sensitive to TNF than wild-type cells. Our results indicate that TNF induces PARP activation leading to ATP depletion and subsequent necrosis. In contrast, in CD95-mediated apoptosis caspases cause PARP-1 cleavage and thereby maintain ATP levels. Because ATP is required for apoptosis, we suggest that PARP-1 cleavage functions as a molecular switch between apoptotic and necrotic modes of death receptor-induced cell death. INTRODUCTIONTwo forms of cell death, namely apoptosis and necrosis, are distinguished by morphological and biochemical features. Although apoptosis accounts for most of physiological cell death, necrosis is usually induced in pathological situations by accidental and acute damage to cells (Kerr et al., 1972;Wyllie et al., 1980). Necrosis is characterized by cell swelling and disruption of the cell membrane, leading to the release of the cellular content, which may result in an inflammatory response (Fiers et al., 1999). In contrast, apoptosis is a tightly regulated process controlled by a hierarchical set of molecules that were originally identified in Caenorhabditis elegans and later in mammalian cells (Cohen, 1997;Cryns and Yuan;Los et al., 1999). The apoptotic cascade has been intensively studied for death receptors such as TNF receptor-1 (TNF-R1) and CD95 (APO-1/Fas) . After death ligands bind to their cognate receptors, several prominent biochemical events occur including the proteolytic activation of caspases as the critical executioners of apoptosis and the internucleosomal fragmentation of DNA that is mediated by cleavage of DNA fragmentation factor (DFF45/ICAD) (Los et al., 1995;Muzio et al., 1996;Liu et al., 1997;Enari et al., 1998).Another characteristic event of apoptosis is the proteolytic cleavage of poly(ADP-ribose)polymerase-1 (PARP-1), a nuclear enzyme involved in DNA repair, DNA stability, and transcriptional regulation. Caspases, in particular caspase-3 and -7, cleave the 116-kDa form of PARP-1 at the DEVD site to generate a 85-and a 24-kDa fragment (Kaufmann et al., 1993;L...

The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16 Ink4a , p15 Ink4b , p18 Ink4c , p19 Ink4d ), and the Cip1/Waf1/Kip1-2-family (p21 Cip1/Waf1 , p27 Kip1 , p57 Kip2 ) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X L Mcl-1 L ; Bax, Bok/Mtd, Bak, and Bcl-X S ; Bad, Bid, Bim EL , Bmf, Mcl-1 S ) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G 1 -S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.