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The apoptosome: emerging insights and new potential targets for drug design.

D'Amelio M, Tino E, Cecconi F - Pharm. Res. (2007)

Bottom Line: Apoptosis plays a crucial role in tissue homeostasis, development and many diseases.Consequently, great interest has emerged in devising therapeutic strategies for regulating the key molecules involved in the life-and-death decision.Here we review recent progress in apoptosis-based pharmacological therapies and, in particular, we point out a possible role of the apoptosome as an emerging and promising pharmacological target.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143, Rome, Italy.

ABSTRACT
Apoptosis plays a crucial role in tissue homeostasis, development and many diseases. The relevance of Apaf1, the molecular core of apoptosome, has been underlined in mitochondria-dependent apoptosis, which according to a growing body of evidence, is involved in various pathologies where the equilibrium of life-and-death is dysregulated, such as heart attack, stroke, liver failure, cancer and autoimmune diseases. Consequently, great interest has emerged in devising therapeutic strategies for regulating the key molecules involved in the life-and-death decision. Here we review recent progress in apoptosis-based pharmacological therapies and, in particular, we point out a possible role of the apoptosome as an emerging and promising pharmacological target.

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Apoptosis signalling pathways. Two important pathways of caspase activation exist in mammalian cells, one involving death receptor and the other involving mitochondria (see also text); (→ activation; ⊣ inhibition). The extrinsic cell death pathway (dotted line) is mediated by death receptors (the best studied death receptor is Fas).The binding of Fas ligand (FasL) leads to receptor activation. The Fas receptor contains a death domain (DD) in its cytoplasmic region which interacts with the adaptor protein (FADD), forming the DISC (Death-Inducing Signalling Complex). DISC formation results in the activation of caspase-8,-10 which in turn will activate downstream effector caspase (caspase-3,-7). In the mitochondrial pathway (continuous line), which is initiated by multiple forms of cellular stress, Bax and Bak are activated at mitochondria. Also, Bid (activated by caspase-8 cleaveage in extrinsic cell death pathway) activates Bax and Bak to mediate the release of cytochrome c in the cytosol. Cytochrome c and dATP trigger the assembly of the Apaf1-apoptosome, which recruits and activates caspase-9. This, in turn, cleaves and activates caspase-3. The activation of caspase-3, -7 is antagonized by IAPs, which in turn can be inhibited by Smac/DIABLO and Omi/HtrA2.
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Fig1: Apoptosis signalling pathways. Two important pathways of caspase activation exist in mammalian cells, one involving death receptor and the other involving mitochondria (see also text); (→ activation; ⊣ inhibition). The extrinsic cell death pathway (dotted line) is mediated by death receptors (the best studied death receptor is Fas).The binding of Fas ligand (FasL) leads to receptor activation. The Fas receptor contains a death domain (DD) in its cytoplasmic region which interacts with the adaptor protein (FADD), forming the DISC (Death-Inducing Signalling Complex). DISC formation results in the activation of caspase-8,-10 which in turn will activate downstream effector caspase (caspase-3,-7). In the mitochondrial pathway (continuous line), which is initiated by multiple forms of cellular stress, Bax and Bak are activated at mitochondria. Also, Bid (activated by caspase-8 cleaveage in extrinsic cell death pathway) activates Bax and Bak to mediate the release of cytochrome c in the cytosol. Cytochrome c and dATP trigger the assembly of the Apaf1-apoptosome, which recruits and activates caspase-9. This, in turn, cleaves and activates caspase-3. The activation of caspase-3, -7 is antagonized by IAPs, which in turn can be inhibited by Smac/DIABLO and Omi/HtrA2.

Mentions: As outlined above, apoptosis is a cellular process which leads to cytoskeletal and nuclear proteolytic digestion. These typical features are the consequence of activation of a family of proteases called caspases, which are produced as zymogenes. Based on the activation order in cell death pathways, caspases are divided into two major groups: executioner caspases and initiator caspases (2). The executioner caspases, caspase-3, -6 and -7 in mammals, cleave selected substrates to produce the typical alteration changes associated with apoptosis. The executioner caspases are activated by initiator caspases, including caspase-8, -9 and -10. By examining the patterns of caspase activation following different apoptotic stimuli, two main pathways have emerged: the death receptor pathway (extrinsic pathway) and the mitochondrial pathway (intrinsic pathway; 3,4) (Fig. 1).Fig. 1


The apoptosome: emerging insights and new potential targets for drug design.

D'Amelio M, Tino E, Cecconi F - Pharm. Res. (2007)

Apoptosis signalling pathways. Two important pathways of caspase activation exist in mammalian cells, one involving death receptor and the other involving mitochondria (see also text); (→ activation; ⊣ inhibition). The extrinsic cell death pathway (dotted line) is mediated by death receptors (the best studied death receptor is Fas).The binding of Fas ligand (FasL) leads to receptor activation. The Fas receptor contains a death domain (DD) in its cytoplasmic region which interacts with the adaptor protein (FADD), forming the DISC (Death-Inducing Signalling Complex). DISC formation results in the activation of caspase-8,-10 which in turn will activate downstream effector caspase (caspase-3,-7). In the mitochondrial pathway (continuous line), which is initiated by multiple forms of cellular stress, Bax and Bak are activated at mitochondria. Also, Bid (activated by caspase-8 cleaveage in extrinsic cell death pathway) activates Bax and Bak to mediate the release of cytochrome c in the cytosol. Cytochrome c and dATP trigger the assembly of the Apaf1-apoptosome, which recruits and activates caspase-9. This, in turn, cleaves and activates caspase-3. The activation of caspase-3, -7 is antagonized by IAPs, which in turn can be inhibited by Smac/DIABLO and Omi/HtrA2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2279152&req=5

Fig1: Apoptosis signalling pathways. Two important pathways of caspase activation exist in mammalian cells, one involving death receptor and the other involving mitochondria (see also text); (→ activation; ⊣ inhibition). The extrinsic cell death pathway (dotted line) is mediated by death receptors (the best studied death receptor is Fas).The binding of Fas ligand (FasL) leads to receptor activation. The Fas receptor contains a death domain (DD) in its cytoplasmic region which interacts with the adaptor protein (FADD), forming the DISC (Death-Inducing Signalling Complex). DISC formation results in the activation of caspase-8,-10 which in turn will activate downstream effector caspase (caspase-3,-7). In the mitochondrial pathway (continuous line), which is initiated by multiple forms of cellular stress, Bax and Bak are activated at mitochondria. Also, Bid (activated by caspase-8 cleaveage in extrinsic cell death pathway) activates Bax and Bak to mediate the release of cytochrome c in the cytosol. Cytochrome c and dATP trigger the assembly of the Apaf1-apoptosome, which recruits and activates caspase-9. This, in turn, cleaves and activates caspase-3. The activation of caspase-3, -7 is antagonized by IAPs, which in turn can be inhibited by Smac/DIABLO and Omi/HtrA2.
Mentions: As outlined above, apoptosis is a cellular process which leads to cytoskeletal and nuclear proteolytic digestion. These typical features are the consequence of activation of a family of proteases called caspases, which are produced as zymogenes. Based on the activation order in cell death pathways, caspases are divided into two major groups: executioner caspases and initiator caspases (2). The executioner caspases, caspase-3, -6 and -7 in mammals, cleave selected substrates to produce the typical alteration changes associated with apoptosis. The executioner caspases are activated by initiator caspases, including caspase-8, -9 and -10. By examining the patterns of caspase activation following different apoptotic stimuli, two main pathways have emerged: the death receptor pathway (extrinsic pathway) and the mitochondrial pathway (intrinsic pathway; 3,4) (Fig. 1).Fig. 1

Bottom Line: Apoptosis plays a crucial role in tissue homeostasis, development and many diseases.Consequently, great interest has emerged in devising therapeutic strategies for regulating the key molecules involved in the life-and-death decision.Here we review recent progress in apoptosis-based pharmacological therapies and, in particular, we point out a possible role of the apoptosome as an emerging and promising pharmacological target.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143, Rome, Italy.

ABSTRACT
Apoptosis plays a crucial role in tissue homeostasis, development and many diseases. The relevance of Apaf1, the molecular core of apoptosome, has been underlined in mitochondria-dependent apoptosis, which according to a growing body of evidence, is involved in various pathologies where the equilibrium of life-and-death is dysregulated, such as heart attack, stroke, liver failure, cancer and autoimmune diseases. Consequently, great interest has emerged in devising therapeutic strategies for regulating the key molecules involved in the life-and-death decision. Here we review recent progress in apoptosis-based pharmacological therapies and, in particular, we point out a possible role of the apoptosome as an emerging and promising pharmacological target.

Show MeSH
Related in: MedlinePlus