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Physiological and Pathological Roles of Apaf1 and the Apoptosome

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Physiological and Pathological Roles of Apaf1 and the Apoptosome J.Cell.Mol.Med. Vol 7, No 1, 2003 pp. 21-34 Apoptosis Review Series Physiological and pathological roles of Apaf1 and the apoptosome E. Ferraro, M. Corvaro, F. Cecconi * Dulbecco Telethon Institute at the Department of Biology, University of Tor Vergata, Rome, Italy Received: January 9, 2003; Accepted: February 20, 2003 • Introduction • Key proteins in neurodegenerations • Apoptosome and Apaf1 can be substrates of caspases • Apaf1 roles in development • Caspases are activated in brains of • Apaf1 dosage effect patients with neurodegenerations • Role of Apaf1 in cancer - Evidence of caspase activation and • Apaf1 as a tumor suppresor gene other apoptotic features in in vivo • Evidences of Apaf1 dysfunction in cancer and in vitro models of neurodegenerations • Apaf1 regulation: importance of Apaf1 - Loss of connectivity and caspases dosage in cancer - Many pathways to explain the confusion • Importance of apoptosome components - Cell death in onset or progression of in cancer neurodegenerations? • Neurodegenerations and apoptosis • Conclusive remarks Abstract Different cellular pathways can lead to apoptosis. Apaf1 is the molecular core of the apoptosome, a multiproteic com- plex mediating the so-called mitochondrial pathway of cell death. The importance of this pathway during develop- ment has been clearly demonstrated by knocking out key genes. Also, the relevance of Apaf1 dosage during devel- opment has been recently underlined. Moreover, a growing body of evidences seems to point out a possible role of the mitochondria-dependent apoptosis in different pathologies. In particular, we discuss here some recent evidences regarding the putative role of the apoptosome in neurodegeneration and cancer. Keywords: apoptosis • cell death • neurodegeneration • Apaf1 • apoptosome • caspases * Correspondence to: Dr. F. CECCONI Via della Ricerca Scientifica s.n.c., 00133, Rome, Italy. Dulbecco Telethon Institute at the Department of Biology - Tel.: 0039-06-72594319, Fax: 0039-06-2023500. University of Tor Vergata E-mail: [email protected] Introduction tosome which, in turn, binds and activates procas- pase-9 [6] (Fig 1). The apoptosome is the execution- Apoptosis is a form of cell death essential for tissue er of the mitochondria-dependent apoptosis. Apaf1 is homeostasis and development. It is also used as a cel- the core of the apoptosome. Recent evidences suggest lular response to stress or pathogens. Deregulated that the apoptosome is a wheel-like particle contain- apoptosis can contribute to many forms of human dis- ing seven Apaf1 monomers which, like seven spokes, eases such as cancer, autoimmunity, heart disease, radiate from a central hub [7]. Apaf1 possesses an immunodeficiencies and neurodegenerative disor- amino-terminal CARD domain (interacting with the ders. CARD domain of procaspase-9), a central CED-4- Cells undergoing apoptosis show characteristic like domain (which contains Walkers A and B boxes morphological features such as cell shrinkage, mem- for nucleotide binding) and a long carboxy-terminal brane blebbing, chromatin condensation, DNA frag- domain extremely rich in WD-40 repeats. The CARD mentation and breakdown into apoptotic bodies that domain is located in the central hub. The cytochrome are rapidly phagocytosed [1, 2]. c would interact with the WD40 domain, which forms Most of these typical features are the consequence the distal part of the spoke. Normally Apaf1 has a of caspases activation. Caspases are a group of cys- compact autoinhibited shape in which the CARD teine proteases with specificity for aspartic acid domain binds the WD40 domain. Following its residues. To date, 14 mammalian caspases have been release from mitochondria, the cytochrome c dis- identified. They are expressed as inactive proenzymes places the CARD domain from the WD40 domain and proteolitically activated to form active tetramers taking its place and allowing the CED-4 homology during apoptosis. Many caspases participate in sig- domain to bind dATP/ATP and undergo a conforma- naling and execution of apoptosis while others are tional change in which Apaf1 has a more extended implicated in proinflammatory mechanisms [3]. conformation; this is required for efficient assembly Stimuli that trigger apoptosis are diverse and appear of the apoptosome and procaspase-9 binding to the to engage the cell death machinery in a variety of exposed CARD domain [7]. ways. However, in many cases, signals generated by The mechanism of procaspase-9 activation is not numerous death-promoting agents all converge, at clear. Mature caspase-9 remains bound to the apopto- some point, on mitochondria and trigger release of some where it recruits and activates executioner cas- important pro-apoptotic factors from this organelle, pases such as caspase-3 and caspase-7 [7]. defining the so-called mitochondrial pathway of cell The activation of caspases requires the removal of death [4, 5]. The Bcl2 family (which includes pro- IAPs (inhibitor of apoptotic proteins) which bind cas- apoptotic and anti-apoptotic members) of proteins pases. One of these, XIAP, directly interacts with the regulates the release of apoptogenic factors from apoptosome by associating and inhibiting caspase-9 mitochondria. The mechanism of this process is still and caspase-3 [8, 9]. Another protein released from unclear. It might involve the formation of specific mitochondria, Smac/Diablo, promotes apoptosis by pores or the rupture of the outer membrane which can binding to IAPs and removing their inhibitory activi- be direct or mediated by the opening of the mito- ty on caspases [10]. Omi/HtrA2 (a proapoptotic mito- chondrial permeability transition pore (MPTP) fol- chodrial factor) can also induce apoptosis in a cas- lowed by swelling of the matrix and subsequent dis- pase-dependent manner via its ability to disrupt cas- ruption of the outer membrane [4, 5]. pase-IAPs interaction and in a caspase-independent manner through its serine protease activity [11]. Once activated, executioner caspases cleave a wide variety of cellular substrates leading to the orderly demise of Apoptosome and Apaf1 the cell. Apaf1 can interact with other proteins, which reg- One of the pro-apoptotic factors released from mito- ulate its function. It has been shown that Hsp70 can chondria during apoptosis is the cytochrome c. In the bind to Apaf1 and prevent recruitment of procaspase- cytosol, the cytochrome c binds the adapter molecule 9 to the apoptosome [12]. Hsp90 can form a cytoso- Apaf1 and, in the presence of ATP/dATP, it promotes lic complex with Apaf1 inhibiting its oligomerization the assembly of a multiproteic complex called apop- and formation of the active apoptosome [13]. Hsp27 22 J.Cell.Mol.Med. Vol 7, No 1, 2003 Fig. 1 The activation of the apoptosome. binds cytochrome c preventing its interaction with this direct interaction has been recently questioned Apaf1 [14]. Aven would inhibit apoptosis by binding [15]. Furthermore, some authors reported that Apaf1 Apaf1 and impairing its oligomerization. Diva/Boo is can be proteolitically cleaved by caspase-3, but the an antiapoptotic member of the Bcl2 family; it has significance of this processing has not been clarified been reported to be able to interact with Apaf1 but yet [15]. 23 Apaf1 roles in development phase since in Apaf1 mutant embryos, by e14. 5, vas- cular endothelial cells seem to obliterate completely As main mediator of the mitochondria-dependent the optic cup. apoptosis, Apaf1 plays a crucial role in development. The analysis of the Apaf1-/- phenotype suggests In fact, while no alterations were observed in het- that Apaf1 can be involved also in apoptosis which erozygous mice, Apaf1 deficient embryos die contributes to morphogenetic remodeling of inner ear between embryonic day 16 (e16) and post-natal day 0 in mice. (pn0) [16]. Abnormal Apaf-/- embryos were found at Cell death of early stem cells in the brain is essen- e11.5 and later; they show alterations of the develop- tial for a normal development of the nervous system. ment of many organs [16]. From e12.5 onward, the brain of Apaf1 mutants Dramatic craniofacial alterations are clearly visi- shows important morphological distortions. When ble at e16.5: midline facial cleft, rostral exencephaly, apoptosis is prevented, like in Apaf1 knockouts, a cleft palate and absence of skull vault and of all huge brain overgrowth due to an enlargement of pro- vomer and ethmoidal elements. This phenotype liferative zones is observed as a bilateral protrusion of demonstrates that apoptosis is essential in midline the forebrain or an exencephalic brain mass. This fusion of craniofacial structures. brain hyperplasia is particularly intense in the dien- Apoptosis is needed to remove the interdigital cephalon and midbrain and exerts a pressure on telen- cells of the limbs by e15.5, for the sculpting of the cephalic vesicles, which become misfolded and digits. Apaf1-/- embryos, at this stage, show poorly reduced in size. The obliteration of the lumen of the shaped digits with persistence of interdigital webs neural tube could have as a consequence a certain confirming that Apaf1 is a key component for this degree of hydrocephalia. The enlarged brain, com- process. At e16.5, however, all mutants have a normal pounded by the defect of skull and facial midline cleft development of limbs and show a form of cell death and by the hydrocephalia has, as a final result, the caspase-independent, TUNEL (terminal-deoxynu- exencephaly found in Apaf1 mutants by e16.5. cleotidyl-mediated dUTP nick end
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