cell death Flashcards
how do cells die
-Most cells die through:
=Necrosis: 1 cell dies often induces surrounding cells to die, external damage and pathological
=Apoptosis: very controlled form of cell death
=‘Falling off’
=Programmed cell death
=Cell suicide
=50 billion cells per day
-More than one mechanism may be involved in the death of a cell
When does necrosis occur?
-Physical damage
=Trauma e.g. cuts and burns
=Extreme temperatures e.g. frostbite
-Toxins:
=External e.g. snake venom
=Internal e.g. bacterial toxins
-Acute hypoxia/ischaemia e.g. stroke
When does apoptosis occur?
-Physiological situations:
=Tissue size maintenance
=Developmental cell loss – growth factors
=Removal of immune cells
=Hormone-dependent involution
=Inappropriate interactions - Anoikis
-Pathological situations:
=DNA damage e.g. radiation, oxidative stress
=Virally infected cells
what are the reversible and irreversible characteristics of necrosis
-Reversible:
=Membrane integrity compromised
=Organelle and cell swelling
-Irreversible:
=Increased intracellular calcium
=Autolysis- release of enzymes in cells
=Cell bursting (cell lysis)
=Elicits an inflammatory response
what are some Characteristics of apoptosis
-Shrinkage
-Nuclear breakdown
-Apoptotic bodies
-Phagocytosis
-No inflammatory response
-Requires energy
-Controlled cell death
-Relationship with autophagy- damaged proteins and organelles removed from cells
how do necrosis and apoptosis play a role in Brain ischaemia
-Both may be involved in the death of cells during an event
-Cells in middle die through necrosis
-Cells at edge die through apoptosis
-This restricts spread of cell death
whats developmental apoptosis and whats an example
-Developmental apoptosis is very controlled
-Think about you organs and how, for example, your liver is the same shape as someone else’s. You tissues/organs don’t just randomly grow
-C. elegans- Nematode worm, 1mm long with ~1100 cells, 131 die in development
-Digit formation in mice: Apoptosis is initiated through release of local signal proteins
-Not enough survival factor = apoptosis
- Neuronal connections are refined by the competition for survival factors
apoptosis
-Regulation: Genetic programmed
-Control: Controlled
-Cell shape: Shrinkage, condensed
-Plasma membrane integrity: Maintained
-Cellular process: Budding
-Cellular content: Packaged in apoptotic bodies
-DNA: Fragmentation, chromatin condensation
-Energy: ATP required
-inflammatory response: Absent
-Mediator: Caspase
necrosis
-Regulation: Ischemia, trauma or ATP depletion
Control: Uncontrolled
- Cell shape: Swelling
-Plasma membrane integrity: Collapsed
-Cellular process: Blebbing
- Cellular content: Leakage to extracellular fluid
-DNA: No fragmentation
-Energy: Not required
-Inflammatory response: Present
-Mediator: Caspase-independent
what are Ced Genes
-C-elegans provide an excellent model for studying apoptotic pathways
-Ced genes involved from recognition of apoptotic signal to engulfment of apoptotic cell by phagocytes
-Many C.elegans genes are conserved in mammals:
=EGL-1 -> BH3-only proteins
=Ced 9 ->Bcl-2
=Ced 4 -> APAF-1
=Ced 3 -> caspases
-Pro- and anti- apoptotic genes:
=decrease Ced 3 or 4 gives excess adult cells
=decrease Ced 9 gives massive cell death
what are caspases
-The executioners of cell death = essential for apoptosis
-C = cysteine at their active site
asp = aspartic acids are the cleavage site in target proteins
-Irreversible pathway when activated
-10+ ced-3 homologues
what are Initiator and executioner caspases
-Initiator caspases:
=activated by apoptotic signals
=activate executioner caspases
-Executioner caspases:
=cleave >1000 proteins
-Amplifying proteolytic cascade:
=one initiator caspase can activate multiple executioner caspases
-Spitting initiator and executioner gives the cell control options
what are caspase targets
-Cause breakdown of nucleus structure, including the nuclear lamina through cleavage of nuclear lamins- nuclear membrane integrity destroyed
-Prevents DNA repair by cleaving the DNA repair enzyme PARP (Poly ADP-ribose polymerase) - so no longer function properly
-Cause cytoskeletal changes, for example the breakdown of actin, by cleaving cytoskeletal proteins like Gelsolin
what are the Two main ways of initiating apoptosis
-Extrinsic pathway
-Intrinsic pathway
whats the extrinsic pathway of initiating apoptosis
-Tumour necrosis factor family
-6 related receptors – the death receptors
-Indirectly (via the DISC) activate initiator caspases
-DISC: Death-inducing signalling complex This is a multi-protein complex formed by members of the “death receptor” family of apoptosis-inducing cellular receptors
whats the intrinsic pathway of initiating apoptosis
-Triggered by:
=stress signals e.g. DNA damage
=developmental signals
-Example:
=cytochrome C release from mitochondrion
=Adaptor protein = Apaf-1 = apoptotic protease activating factor
=Caspase-9 = initiator caspase
What decides whether cytochrome c or other intermembrane mitochondrial proteins are released in the intrinsic pathway
-Balance between pro- and anti-apoptotic factors known as Bcl2 family proteins
-EGL-1 homologue BH3-only protein = pro-apoptotic
-Ced9 homologue Bcl2 protein = anti-apoptotic
simple intrinsic pathway
-DNA damage & p53
-Mitochondria/Cytochrome C
-Initiator Caspase 9
-Effector Caspase 3
-apoptosis
simple extrinsic pathway
-death ligands
-death receptors
-initiator caspase 8
-Effector Caspase 3
-apoptosis
