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APOPTOSIS

APOPTOSIS: Overall scheme


APOPTOSIS: Related diseases & proteins



DEATH PATHWAYS: APOPTOSIS vs NECROSIS
PATHOLOGICAL FEATURES
Apoptosis Necrosis
Patterns of death Single cells Groups of,
  or single, cells
Cell size Shrinkage
Fragmentation
Swelling
  (Oncosis)
Plasma membrane Preserved continuity
Blebbed
Phosphatidylserine on surface
Smoothing
Lysis: Early
Mitochondria Increased membrane permeability
Contents released into cytoplasm
  Cytochrome c; Apaf1
Structure relatively preserved
Swelling
Disordered structure
Organelles Contracted
"Apoptotic bodies"
Swelling; Loss
Disruption
Nuclei Chromatin:
  Clumps & Fragmented
Membrane disruption
DNA degradation Fragmented
  Internucleosomal cleavage
  Free 3' ends
  Laddering on electrophoresis
DNA appears in cytoplasm
Diffuse & Random
Cell degradation Phagocytosis
No inflammation
Inflammation
Macrophage invasion
MECHANISMS
General stimuli Developmental programs
  Endogenous signals
  Intercellular signals
Disease processes
Disease processes
Specific stimuli Growth factor deprivation: NGF; IL-2
Death activators: Bind to surface receptors
  Cytokines: TNF-α; Lymphotoxin
  Fas ligand
  TRAIL
Toxic: Hormones; Radiation; Ischemia, mild
Oxidants in cell: Increased
DNA damage
Toxic
Ischemia, severe
Radiation
Cellular processes Programmed cascade of reactions
  Caspase activation
  Internucleosomal endonucleases
  Transglutaminase activation
Requires
  New RNA transcription
  Protein synthesis
  ATP
No protein synthesis
No RNA transcription
Energy independent
ATP depletion
Apoptosis
  Inhibitors
Protease inhibitors
  NAIP ; crmA; p35 ; XIAP
  HIAP-1 ; IAP-2 ; IAP3
Bcl-2 family (Some)
  Bcl-2 ; Mcl-1 ; Bcl-w ;
  Bcl-xL EGLN3
Apoptosis
  Promoters
Bcl-2 family (Some)
  Bax ; Bcl-xS; Hrk ; Bak ;
  Bid ; Bik ; Bad

CASPASES: Cysteine Aspartate Specific ProteASEs

General characteristics

Caspase types: Based on sequence of activation in apoptosis


Class Name Regulatory
unit
Adapter
molecule
Optimal
tetrapeptide
Activators Caspase-2 CARD RAIDD DXXD
Caspase-8 DED FADD (I/V/L)EXD
Caspase-9 CARD Apaf-1 (I/V/L)EHD
Caspase-10 DED FADD (I/V/L)EXD
Executioners Caspase-3 DEXD
Caspase-6 (I/V/L)EXD
Caspase-7 DEXD
Cytokine processors Caspase-1 CARD CARDIAK (W/Y/F)EHD
Caspase-4 CARD (W/Y/F)EHD
Caspase-5 (W/Y/F)EHD
mCaspase-11
mCaspase-12
Caspase-13
mCaspase-14
CARD: Caspase recruitment domain
DED: Death effector domain


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References
1. NEJM 1996;335:1897-1905
2. Human Mutation 1999;13:87-98
3. Immunol Today 1997;18:189-198
4. FASEB J 1997;11;1067-1075
5. Cell Mol Life Sci 1998;54:253-262
6. J Neuroimmunol 1999;94:1-14
7. Annu. Rev. Immunol. 1999;17:739-779
8. Human Mutation 1999;14:199-215

8/28/2014