Apoptosis
-
Upload
najmaldin-saki -
Category
Technology
-
view
10 -
download
3
description
Transcript of Apoptosis
![Page 1: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/1.jpg)
Apoptosis
By : najmaldin saki2008
Department of Hematology School of Medical
Sciences Tarbiat Modares University
![Page 2: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/2.jpg)
![Page 3: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/3.jpg)
![Page 4: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/4.jpg)
![Page 5: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/5.jpg)
![Page 6: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/6.jpg)
![Page 7: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/7.jpg)
Caspases
![Page 8: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/8.jpg)
Ligand-induced cell deathLigand-induced cell death
“The death receptors”
Ligand-induced trimerization
Death Domains
Death Effectors
Induced proximity of Caspase 8
Activation of Caspase 8
FasL
Trail
TNF
![Page 9: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/9.jpg)
CASPASES CAN BE INHIBITED BY VIRUSESCASPASES CAN BE INHIBITED BY VIRUSES
... CrmA
... Baculovirüs p35
... Ebstein Barr Virüs BHRFI proteini
... Ebstein Barr Virüs LMP-1 proteini
![Page 10: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/10.jpg)
3 mechanisms of caspase activationa. 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
![Page 11: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/11.jpg)
Bcl-XL
Bad
Bcl-XL
BaxBcl-2
Bax
Bax Bax
Bcl-2
Bad
CELL SURVIVAL
CELL DEATH
![Page 12: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/12.jpg)
![Page 13: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/13.jpg)
Controlling the cell-proliferation Controlling the cell-proliferation and death machineryand 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.
![Page 14: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/14.jpg)
The bcl-2 family
BH4 BH3 BH1 BH2 TMN C
Receptor domain
phosphorylation
Raf-1calcineurin Pore
formation
Membraneanchor
Liganddomain
Group I
Group II
Group III
Bcl-2
bax
Badbidbik
![Page 15: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/15.jpg)
Bcl-2 ProteinBcl-2 Protein(with BH3 Peptide)(with BH3 Peptide)Bcl-2 ProteinBcl-2 Protein
![Page 16: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/16.jpg)
![Page 17: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/17.jpg)
![Page 18: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/18.jpg)
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 , TNFα, BCL2)
![Page 19: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/19.jpg)
Models of platelet apoptosis
1. apoptosis of platelets was induced by the calcium ionophores ionomycin , A23187 which induce apoptosis in nucleate cells.
2. 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
3. apoptosis was induced by platelet aging in vitro during storage of leukodepleted platelet concentrates (PCs) under standard blood banking conditions at 22 C
4. apoptosis was associated with platelet aging in vivo in dogs with thrombopoiesis suppressed by estradiol injection .
5. platelet apoptosis was reported in mice with thrombocytopenia caused by malaria infection and induced by injection of TNF or anti-platelet antibodies
![Page 20: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/20.jpg)
Apoptotic changes in platelet morphology
These morphologic changes included:
platelet shrinkagecytoplasm condensationplasma 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.
![Page 21: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/21.jpg)
![Page 22: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/22.jpg)
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 e ect on platelets.ff
![Page 23: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/23.jpg)
ᴪm
In normal undamaged nucleate cells, mitochondria have a high ᴪm; breakdown of ᴪm is characteristic of early apoptosis .
ᴪm in platelets can be measured by the cell-permeable lipophilic cationic dyes JC-1 and DiOC6 .
Using JC-1 , we have demonstrated depolarization of ᴪm in PCs starting from days
13_14 of storage.
![Page 24: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/24.jpg)
Cytochrome c, Diablo/Smac and Apaf-1.
Cytochrome C and Apaf-1 have been found by immunoblot in whole lysates of fresh nonactivated platelets.
![Page 25: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/25.jpg)
![Page 26: Apoptosis](https://reader033.fdocuments.us/reader033/viewer/2022061110/544f2a4aaf7959fb6f8b55dd/html5/thumbnails/26.jpg)