Cell Death Flashcards
What are the two main forms of cell deah
Apoptosis
Necrosis
What is apoptosis?
Programmed cell death
What is necrosis?
Cell death by injury
When does apoptosis occur?
Development
Immune response - destruction of excess cells
Cancer therapy - eliminate tumour cells
What happens if there is too much apoptosis?
Neurodegenerative disease
What are the features of an apoptotic cell?
- Cell compaction
- Blebbing and scrambling of membranes
- Chromatin condensation
- DNA fragmentation
- Cell fragmentation into membrane bound pieces
- Engulfment by macrophages
Does apoptosis trigger an inflammatory response?
No
Does necrosis trigger an inflammatory response?
Yes
What causes the inflammatory response in necrosis?
Neutrophils, macrophages and other innate cells
What is the inflammatory system alerted by in necrosis?
Danger signals released by dying cells (DAMPs)
What are the morphological features of necrosis?
- Increasing translucent cytoplasm
- Swelling of organelles
- Condensation of chromatin into small patches
- Increased cell volume leading to disruption of plasma membrane
Why does a cell undergo apoptosis
- if a cell has sustained a large amount of damage which cannot be repaired or would take a large amount of energy to do so
- the cell has outlived it’s usefulness
- the cell has become senescent
- the death of the cell is needed for the organism to reach it’s final embryonic development
- the death of a cell is necessary for maintaining part of a physiological process of an organism
Syndactylyl
The cells in the interdigital space which have failed to undergo apoptosis and therefore the outcome is that the foetus is born with webbed hands and feet
Which cell can be used for apoptosis?
cytotoxic T cells
how are initiator caspases activated?
Protein:protein interactions
How are effector caspases activated?
proteolytic cleavage
During apoptosis activation, where does proteolytic cleavage occur?
Death-effector domain
Where are death effector domains present?
Procaspases
Proteins which regulate caspase activity
Give an example of a protein which regulates caspase activity
FAS-associating death domain-containing protein (FADD)
Function of FADD
recruits procaspase 8 and 10 to the death induced signalling complex (DISC)
How does procaspase recruitment occur
The interaction between DED of the procaspase and the adaptor molecules associated with TNF receptor
Function of caspase 3
Cuts DNA
Function of caspase 6
mediates nuclear shrinkage during inflammation
Function of caspase 8
linked to two cells which are together, if one is not functional then the signal is sent to caspase 8
Function of caspase 9
releases cytochrome C, binds to Apaf-1 with dATP
What is the extrinsic apoptotic pathway?
Fas ligand binds to Fas receptor
Recruitment of Caspase 8 through DED domains to the adaptor protein
Activate Caspase 3
Effect of activation of caspase 3
- inhibition of flippase and activation of scramblase
- Actin cleavage
- inhibit PARP = no DNA repair
- ICAD activation -> CAD -> chromatin condensation and DNA fragmentation
Function of scramblase
translocate phospholipids between the two monolayers of a lipid bilayer and this allows the cell to be eaten by macrophages
Examples of BCL-2 pro-apoptotic proteins
- Bax
- Bak
Examples of BCL-2 anti-apoptotic proteins
- BCL-2
- BCLxL
- MCL-1
Where are BCL-2 pro-apoptotic proteins found?
Endoplasmic reticulum
Where are the BCL-2 anti-apoptotic proteins found?
Mitochondria
What is the function of BH3 only proteins?
Control the interaction between anti- and pro- apoptotic proteins
What does BH3 stand for?
BCL-2 homology domain 3
Where does BCL get it’s name from?
B-cell lymphoma
Examples of BH3 only proteins?
- Bid
- Bad
Function of Bax and Bak
oligmoerise and cause mitochondrial outer membrane depolarisation and permeabilisation, releasing cytochrome C in the cytoplasm that will bind to Apaf1 and caspase 9 to form an apoptosome
What is Apaf1?
Apoptotic protease activating factor
What does Apaf-1 exist as?
Inactive monomer in the cytoplasm
What is an apoptosome?
Apaf-1-cytochrome C heterodimer
Requires the conversion of dATP/ATP to dADP/ADP
What happens to the nucleus during apoptosis?
Fragmentation of DNA
Inactivation of enzymes involved in DNA repair
Breakdown of structural nuclear proteins
How does DNA fragmentation occur?
Fragmented into nucleosomal units is caused by CAD (caspase activated Dnase)
How does CAD exist in the inactive form?
as ICAD
What enzyme which is involved in DNA repair is inhibited during apoptosis?
poly(ADP-ribose)polymerase (PARP)
What structural nuclear proteins are broken down during apoptosis?
Laminins by caspase 6
Whats binds to phosphatiyl serine?
Mfg-E8 and Annexin I
Annexin V
What are Mf8-E8 and Annexin I
Targets for macrophages
Function of annexin V
tool to detect apoptotic cells
4 stages of phagocytosis of apoptotic cells
1) Recruitment of ‘find me’ signals
2) Recognition of newly-exposed ‘eat-me’ signals and endocytosis
3) Breakdown through formation of phagolysosomes
4) Antigen presention
