Beruflich Dokumente
Kultur Dokumente
*Animal Genetics and Breeding Division, #Animal Biochemistry Division, National Dairy Research Institute, Karnal-132001, Haryana, India $College of Applied Education and Health Sciences, Meerut, U.P.
INTRODUCTION
Cell death by injury
-Mechanical damage -Exposure to toxic chemicals
Conted..
Apoptosis or programmed cell death, is carefully coordinated collapse of cell, protein degradation , DNA fragmentation followed by rapid engulfment of corpses by neighbouring cells. (Tommi, 2002)
Essential part of life for every multicellular organism from worms to humans. (Faddy et al.,1992) Apoptosis plays a major role from embryonic development to senescence.
Cancer cells
1930-40
1948-49 1955
Studies of metamorphosis
Cell death in chick limb & exploration of NGF Beginning of studies of lysomes
1964-66
1971 1977
1980-82
1989-91
NECROSIS Vs APOPTOSIS
Wilde, 1999
Apoptosis
Cellular condensation Membranes remain intact Requires ATP Cell is phagocytosed, no tissue reaction Ladder-like DNA fragmentation In vivo, individual cells appear affected
STAGES OF APOPTOSIS
APOPTOSIS: Morphology
organelle membrane blebbing & changes mitochondrial leakage
reduction
cell
shrinkage
nuclear fragmentation
chromatin condensation
Hacker., 2000
Apoptotic body
MF
MF
Caenorhabditis elegans
1090 cells
decision to die
131 cells
execution
engulfment
apoptosis
degradation
ced-3 ced-4
egl-1
ced-9
nuc-1
ces-2
ces-1
Apoptosis: Pathways
Extrinsic Pathway
Death Ligands Death Receptors
Initiator Caspase 8
Effector Caspase 3
Intrinsic Pathway
PCD
Mitochondria/ Cytochrome C
Initiator Caspase 9
FasL Trail
Ligand-induced trimerization
TNF
Apoptotic signals
p53 Internally Cytochrome C driven
mitochondrion
Initiator caspases
6, 8, 9,12
Execution caspases
2, 3, 7
Apoptosis events
Activation
Apoptotic signals
p53 Internally Cytochrome C Bcl2 driven
Initiator caspases
6, 8, 9,12
Survival factors
Execution caspases
2, 3, 7
Apoptosis events
Inhibitors of apoptosis
Inhibition
PI3K
BAD Bcl2
Akt
casp3
Bax
casp9 Apaf1
ATP Cyt.C Smac/ DIABLO
IAPs casp3
H2O2
AIF
Pollack etal., 2001
REGULATION OF APOPTOSIS
Stimuli apoptosis selection of targets
(Rich et al., 2000)
Apoptosis by conflicting signals that scramble the normal status of cell (Canlon & Raff, 1999) Apoptotic stimulicytokines, death factors (FasL)
(Tabibzadeh et al., 1999)
DNA breaks p53 is activated arrest cell cycle or activate self destruction (Blaint & Vousden, 2001)
Importance of Apoptosis
Important in normal physiology / development
Development: Immune systems maturation, Morphogenesis, Neural development Adult: Immune privilege, DNA Damage and wound repair.
Excess apoptosis
Neurodegenerative diseases
Deficient apoptosis
Cancer Autoimmunity
FUTURE PERSPECTIVES
The biological roles of newly identified death receptors and ligands need to be studied
CONCLUSION
an important process of cell death can be initiated extrinsically through death ligands (e.g. TRAIL, FasL) activating initiator caspase 8 through induced proximity. can be initiated intrinsically through DNA damage (via cytochrome c) activating initiator caspase 9 through oligomerization. Initiator caspases 8 and 9 cleave and activate effector caspase 3, which leads to cell death.
DNA DAMAGE
p53
BH4
Raf-1 calcineurin
BH3
BH1
BH2
TM
Membrane anchor
Group I Group II
Group III
If the damage is too extensive then p53 induces gene activation leading to apoptosis (programmed cell death)
BACK
Externally driven
Apoptotic signals
Cytochrome c
Initiator caspases
The immunological synapse holds the cells much tighter together than shown here Fas/ CD95 is the death receptor
Execution caspases
Apoptosis events