Apoptosis


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1 : 1 Reza Ebrahimzadeh M.Sc. Student Medical Genetics Tehran University of Medical Sciences TUMS Apoptosis (Programmed Cell Death ) In The Name Of God
2 : 2 Introduction Highly regulated process that allows a cell to self-degrade Eliminate unwanted or dysfunctional cells Major types of cell death Apoptosis Genome of the cell will fracture Cell shrinkage Very clean and controlled process Content of the cell is kept strictly within the cell membrane as it is degraded Necrosis Cell dies by swelling and bursting its content in the area Causes an inflammatory response
3 : 3 Programmed cell death (PCD) Physiological phenomenon V.s Necrosis Regulated by various signaling pathways Balance between proliferation and differentiation (mammalian organogenesis) PCD has also been associated with pathological processes such as cancer and neurodegeneration
4 : 4 Trigger Apoptosis pathway Extrinsic pathway stimulation of the transmembrane death receptors (such as the Fas receptors, located on the cell membrane ) Intrinsic pathway The release of signal factors within the cell (such as cytochrome c by mitochondrion) Two central pathways are in the process of apoptotic cell death: The activation of the caspase proteases Mitochondrial pathway
5 : 5 Intrinsic pathway The role of mitochondria in apoptosis Several mitochondrial proteins are able to activate apoptosis Reside in the intermembrane space of mitochondria They promote apoptosis either by - Activating caspases and nucleases - neutralizing cytosolic inhibitors Release of cytochrome c Release of Smac Release of apoptosis-inducing factor Release of endonuclease G
6 : 6 Release of cytochrome c Mitochondrial electron transfer chain Release from mitochondria & caspase activation dATP/ ATP + Apaf-1/cytochromec complex apoptosome formation Active caspase 9 Release of Smac Smac/Diablo, a 25-kD mitochondrial protein The first four amino acids of the mature Smac, Ala-Val-Pro-Ile (AVPI), binds to the IAPs [inhibitor of apoptosis proteins] IAP binding results in the inhibition of caspase-9 and caspase-3 activity
7 : 7 Release of apoptosis-inducing factor (AIF) 57-kD flavoprotein Reside mitochondrial intermembrane space AIF is a bifunctional protein - Apoptotic activity - NAD(P)H oxidase activity Translocates from the mitochondria to the nucleus and - chromatin condensation - DNA fragmentation Release of Endonuclease G A known 30-kD nuclease in the mitochondria Participates in mitochondrial replication Eliminating RNA primers? Induce nucleosomal DNA fragmentation
8 : 8 Release of cytochrome c Xiaodong Wang, Genes & Dev. 2001 15: 2922-2933
9 : 9 Cytochrome-c–Apaf-1–caspase-9–caspase-3 pathway Apaf-1 protein from the cytochrome c KO cells remained in the monomeric state Various factors appear activate Apaf-1, including adenovirus E1A and p53
10 : 10 Release of Smac Xiaodong Wang, Genes & Dev. 2001 15: 2922-2933
11 : 11 Jerry M. Adams Genes & Dev. 2003 17: 2481-2495 - The ~20 Bcl-2 family members - Fall into at least three interacting groups
12 : 12 Regulation of mitochondrial apoptotic signals (1) Translocation of the BH3-only family of proteins to mitochondria - Cleavage of Bid - Dephosphorylation of Bad - Disassociation of Bim of microtubule (2) Conformational changes and oligomerization Bax and Bak (3) VDAC and ANT (VDAC: Voltagedependent anion channel ANT: Adenine nucleotidetranslocator) - Form a pore big in outer membrane - Transport across mitochondrial mebrane
13 : 13 The mitochondrial ‘poison cabinet’
14 : 14 Extrinsic pathway Cell surface death receptors and theirs ligands - (TNF-R) superfamily - Cysteine-rich repeat in their extracellular domains, - Death domain, in their cytoplasmic tail Fas/APO-1/CD95, TNFR1, DR-3, DR-4/TRAIL-R1, and DR5/TRAIL-R2
15 : 15 cascade Cytoplasm Caspase Signal Fas ligand Fas receptor Complex
16 : Fas receptor Fas ligand cell membrane DD FADD DED pro - caspase8 active caspase8 DED caspase3
17 : 17 Wesche-Soldato et al.Curr Drug Targets. 2007 April ; 8(4): 493–500.
18 : 18 Role of the ER in apoptosis Major intracellular store of Ca2+ ions Flux of Ca2+ ions & cell death annexin-5, Ca2+ binding, require for apoptosis Cells lacking annexin- 5 failed to release cytochrome c from mitochondria
19 : 19
20 : 20 Caspases Cysteinyl-aspartic-acid-proteases Cleave after certain aspartate residues 14 family member synthesize as zymogens Executioner caspases Initiator caspases Inflamatory caspases
21 : 21 Caspases and receptor cleavage . Archives of Biochemistry and Biophysics 462 (2007) 162–170
22 : 22 Protease domain - Large subunit of 20 kDa - Subunit of approximately 10 kDa Long prodomain - CARD (CAspase Recruitment Domain) e.g., in caspase-2, -9 - DED (Death Effector Domain) e.g., in caspase-8, -10 Small prodomain - Include caspases-3, -6 and -7 Caspase structure
23 : 23 Vascular Pharmacology 46 (2007) 383–393
24 : 24 Caspase function in programmed cell death Cell Death and Differentiation (2007) 14, 32–43 Initiator caspases contain - caspase recruitment domain (CARD) - or a death effector domain (DED)
25 : 25 Caspases biological functions Proinflammatory function - Interleukin-1ß-converting enzyme (ICE) orcaspase 1, 1992 - Also includes caspases 4, 5, 11, 12 Apoptotic function - Central function Cell proliferation - Caspase-8 for proliferation of B, T and NK cells Cell differentiation - Caspase-8 for the differentiation of monocytes
26 : 26 Caspase inhibitors Natural caspases inhibitors - Cowpox virus cytokine response modifier A (CremA) - Baculovirus proteins p53 Caspase-specific inhibitors Fluoromethyl ketones (fmk) Chloromethyl ketones) cmk) Irreversibly alkylate the cysteine residue on the active site of the caspase
27 : 27 Wesche-Soldato et al.Curr Drug Targets. 2007 April ; 8(4): 493–500.
28 : 28 Refrencess Role of mitochondria as the gardens of cell death Cancer Chemother Pharmacol (2005) Exploiting different ways to die Genes & Dev. 2004 18: 1223-1226 Ways of dying: multiple pathways to apoptosis Genes & Dev. 2003 17: 2481-2495 Caspase function in programmed cell death 2007 Nature Publishing Group 14, 32–43 The expanding role of mitochondria in apoptosis Genes & Dev. 2001 15: 2922-2933

 

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Apoptosis
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