Death and Rescue 焉未 知知 生死 Regulation of cardiac myocyte cell death Lin GH
Death and Rescue 未 知 死 焉 知 生 Regulation of cardiac myocyte cell death Lin GH
Death pathway there are two principal forms of cell death: Necrosis apoptosis DEATH STIMULUS e.g.Fas stimulation e.g.ATP depletion aCa8Bar8naeeatsga Irreversible loss of DNA fragmentation Membrane rupture CELDEAT NOELDEROIC
Death pathway there are two principal forms of cell death: Necrosis & apoptosis
Myocyte death as a contributing factor to cardiac pathology A infarction B There is evidence that apoptosis Ischemic Injury and Myocyte Death precedes necrosis and constitutes the prevailing form of myocyte death
Myocyte death as a contributing factor to cardiac pathology Ischemic Injury and Myocyte Death There is evidence that apoptosis precedes necrosis and constitutes the prevailing form of myocyte death. infarction
Initiator caspases Caspase-2 ○☐ Caspase-9 ○ Caspases as the Effector CARD p20 p10 Machinery of Apoptosis Caspase-10●●-☐ Caspase-8 ●●口 DED DED p20 p10 Effector caspases Caspase-3 Caspase-6 Caspase-7 p20p10 Other caspases Caspase-1 Caspase-4 Caspase-5 Caspase-11 Caspase-12 Caspase-13 Caspase-14 CARD p20 p10 cysteine-dependent aspartate-directed proteases
Caspases as the Effector Machinery of Apoptosis Initiator caspases Other caspases Effector caspases cysteine-dependent aspartate-directed proteases
Caspase cascades are highly ordered Caspase-10 Initiator ◆Caspase-8 Caspase-S caspases effector Caspase-3 Caspase-7 caspases Caspase-6 Caspase- Caspase-2 positive feedback
Caspase cascades are highly ordered effector caspases positive feedback Initiator caspases
TABLE 2.Downstream Targets of Caspases Target proteins Nuclear proteins nuclear proteins for caspases Lamin Rb protein DNA-dependent protein kinase 70-kDa subunit of U1 small nuclear ribonucleoprotein Poly(ADP)-ribosylating protein (PARP) Mdm2 Regulatory proteins Regulatory proteins MAPK/ERK kinase kinase 1 (MEKK1) Protein kinase C8 G4-GDI GDP dissociation inhibitor Sterol regulatory element binding protein DNA fragmentation factor/inhibitor of caspase-activated DNAse Cytoskeletal proteins Cytoskeletal proteins DNA fragmen Fodrin Gelsolin Actin Gas2
Target proteins for caspases nuclear proteins Cytoskeletal proteins Regulatory proteins
Apoptotic death pathway Mitochondrion- dependent Intrinsic pathway Receptor- dependent Extrinsic pathway Apoptosis
Apoptotic death pathway Receptordependent Mitochondriondependent Extrinsic pathway Intrinsic pathway
Mechanisms of Caspase Activation Mitochondrion Death receptor 0 nhibition of Activaiono Activation of caspases may take place either within death receptor complexes of the cytoplasmic membrane or by a mitochondrion-dependent mechanism within the cytosol Apoptosis
Mechanisms of Caspase Activation Activation of caspases may take place either within death receptor complexes of the cytoplasmic membrane or by a mitochondrion-dependent mechanism within the cytosol
Death Receptor Pathway NF TNFa ●Death domain TNFRI receptors 0 8sahstiector Death Domain TRADD FADD- NFxB Caspase-8 Caspase-2 Pro-caspase 8 TRAF-2 Signalling Pathway Survival Apoptosis death domain-mediated protein interactions
Death Receptor Pathway death domain-mediated protein interactions
A TNFR1 Fas DR3 DR4 DR5 DR6 NGFR Extracellular Cysteine-rich domains B TNFR1 FADD TRADD OD adapter? +Bd→ Effector caspase activation The extrinsic pathway through death receptors
The extrinsic pathway through death receptors