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    • 1. Apoptosis By : najmaldin saki 2008 Department of Hematology School of Medical Sciences Tarbiat Modares University
    • 2.  
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    • 7. Caspases
    • 8. Ligand-induced cell death “ The death receptors” Ligand-induced trimerization FasL Trail TNF Death Domains Death Effectors Induced proximity of Caspase 8 Activation of Caspase 8
    • 9. CASPASES CAN BE INHIBITED BY VIRUSES ... CrmA ... Baculovirüs p35 ... Ebstein Barr Virüs BHRFI proteini ... Ebstein Barr V irüs LMP-1 proteini
    • 10. 3 mechanisms of caspase activation a. Proteolytic cleavage e.g. pro-caspase 3 b. Induced proximity, e.g. pro-caspase 8 c. Oligomerization, e.g. cyt c, Apaf-1 & caspase 9 Back
    • 11. Bcl-X L Bad Bcl-X L Bax Bcl-2 Bax Bax Bax Bcl-2 Bad CELL SURVIVAL CELL DEATH
    • 12.  
    • 13. Controlling the cell-proliferation and death machinery P53 is able to activate p21 P21 binds to the CDK-cyclin complex and inhibits its protein kinase enzymatic activity
      • - CDK’s target proteins are not phosphorylated
      • - Cell cycle is unable to progress
      • When the DNA mismatches have been repaired,
      • the drop of p53 levels & a cessation of inhibition
      G1-to-S checkpoint block The cell cycle: negative intracellular controls Intracellular signals
      • Fail-safe systems (checkpoints) ensure that the cell cycle does not progress
      • until the cell is competent.
    • 14. The bcl-2 family Receptor domain phosphorylation Raf-1 calcineurin Pore formation Membrane anchor Ligand domain BH4 BH3 BH1 BH2 TM N C Group I Group II Group III Bcl-2 bax Bad bid bik
    • 15. Bcl-2 Protein (with BH3 Peptide) Bcl-2 Protein
    • 16.  
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    • 18.
      • 65000 papers
      • Apoptsis in anucleate platelets wa first reported in 1997 by Vanags et al.
      • It was demonstrated that apoptosis within megakaryocytes & megakaryoblastic is causal for platelet production (NO , TNF α , BCL 2 )
    • 19.
      • Models of platelet apoptosis
      • apoptosis of platelets was induced by the calcium ionophores ionomycin , A23187 which induce apoptosis in nucleate cells.
      • apoptosis was provoked by platelet storage in culture where washed platelets were aged by incubation for 18–24 h at 37 C in a culture medium or plasma in capped tubes
      • apoptosis was induced by platelet aging in vitro during storage of leukodepleted platelet concentrates (PCs) under standard blood banking conditions at 22 C
      • apoptosis was associated with platelet aging in vivo in dogs with thrombopoiesis suppressed by estradiol injection .
      • platelet apoptosis was reported in mice with thrombocytopenia caused by malaria infection and induced by injection of TNF or anti-platelet antibodies
    • 20.
      • Apoptotic changes in platelet morphology
      • These morphologic changes included:
      • platelet shrinkage
      • cytoplasm condensation
      • plasma membrane blebbing
      • extension of filopodia.
      Originaly , these changes were described as “ platelet activation ” and only since 1997 did some investigetors begin to consider these morphologic chenges as apoptotic.
    • 21.  
    • 22. Li et al, found that platelets express mRNA for death ligand TRAIL , death receptors TNFR1, DR3 , DR4 and DR5 , and adapter proteins TRADD and RIP . In contrast , Fas receptor and Fas ligand were not detected in platelets as determined by mRNA and immunoblot and anti-Fas antibodies had no effect on platelets.
    • 23. ᴪ m In normal undamaged nucleate cells, mitochondria have a high ᴪ m; breakdown of ᴪ m is characteristic of early apoptosis . ᴪ m in platelets can be measured by the cell-permeable lipophilic cationic dyes JC-1 and DiOC6 . Using JC-1 , we have demonstrated depolarization of ᴪ m in PCs starting from days 13_14 of storage.
    • 24. Cytochrome c, Diablo/Smac and Apaf-1. Cytochrome C and Apaf-1 have been found by immunoblot in whole lysates of fresh nonactivated platelets.
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    • 26.