Lecture 10: Cell death Flashcards
how do cells die?
Most die through:
- Necrosis
- Apoptosis
- –‘falling of leaves’
- –programmed cell death
- – cell suicide
-More than one mechanism may be involved in the death of a cell
necrosis is characterised by
- Loss of cell components by lysis
- Inflammation
- Autolysis
- Debris (pus)
- (Calcification)
–uncontrolled cell death?
Apoptosis characterised by
- Shrinkage
- Nuclear breakdown
- Phagocytosis
- Requires protein synthesis (cycloheximide-sensitive)
–controlled cell death? (autophagy)
necrosis is associated with
- physical damage
- -gut epithelium
- -drying e.g. nasal epithelium
- -trauma e.g. cuts and burns
- infections
- acute toxicity
- acute hypoxia / ischaemia
- rapid loss cell energy
apoptosis is associated with
- Developmental cell loss
- Senescence
- –Hayflick number
- Chronic toxicity
- Removal of growth factors
- Detachment from substrate
- –(Anoikis - homeless cells)
is it just Necrosis or apoptosis ?
both can occur in the death of a cell.
Brain ischaemia
-cells in the middle die through necrosis
-cells at the edge die through apoptosis
2 mechanisms of apoptosis
- in development
- in the haematopoietic system
developmental apopstosis:
death is common
- metamorphosis e.g. tadpole - frog
- digit formation
- nervous system
CED genes, how many
10+ genes
- recognition to engulfment (most)
- 4 key: RGL-1, Ced 3, Ced 4, Ced 9
decreased Ced 3/4 gives
excess adult cells
decrease Ced 9 gives
massive cell death
ced genes are known as
pro- and anti- apoptotic genes
EGL-1 blocks
Ced 9
Ced 9 blocks Ced 4,
Ced 4 activates Ced 3, Ced 3 triggers cell death
CED genes: mammalian homologues:
- EGL-1 and BH3-only proteins
- Ced 9 and Bcl-2
- Ced 4 and APAF-1
- Ced 3 and the caspases
Caspases are
the executioners of cell death
- no caspase activity, no apoptosis
how many mammalian bed-3 homologues
10 +
- activated by proteolysis
- -cascade affect
- wide range of substrates
- some autocatalytic
Caspase 3 important in development (yama)
Breaks down e.g.
- DNA repair enzyme Poly (ADP-ribose) polymerase (PARP)
- Lamin A
- Huntingtin (Huntingdon’s disease gene product)
Activation of apoptosis:
-Several ways of initiating apoptosis
-Intrinsic and extrinsic pathways
-Tumour necrosis factor family
-5 related receptors – the death receptors
Indirectly (DISC) activate caspases
-Fas-ligand mutations may lead to autoimmune disorders
Intrinsic pathway for apoptosis:
- Cytochrome c release from mitochondria
- Binds apaf-1 and caspase 9
- Triggers caspase cascade
- Numerous triggers for Cy- c release
- Other pro and anti-apoptotic factors involved
- Cells on an apoptotic tightrope
Adults blood cells from
the bone marrow
Progenitors are stimulated by colony-stimulating factors to produce
many offspring.
- Erythropoietin and rbc’s
- Low O2 or rbc count kidney EPO
withdrawal of CFS’s causes
apopstosis
cells defences may be overcome rapidly leading to
necrosis
apoptosis is ___ used
widely used
