Apoptosis Flashcards
apoptosis
programmed cell death
necrosis
cell death by injury
characteristics of apoptosis
- morphological features
- active
- inherently programmed
- can be initiated or inhibited by variety of stimuli
structural changes in apoptosis
- nuclear and cytoplasmic condensation and breaking up of cell into fragments
- apoptotic bodies are shed from epithelial lined surfaces or taken up by other cells where they are degraded by lysosomal enzymes
role of apoptosis in healthy adult tissues
- cell turnover
- focal elimination of cells during normal embryonic development
- occurs spontaneously in untreated malignant neoplasma
- participates in some types of therapeutically induced tumour regression
role of necrosis
- triggers the inflammatory response by neutrophils, macrophages, and other cells of innate immune system
- inflammatory system alerted by danger signals (“alarmins”) released by dying cells: DAMPs (e.g. HMG protein B1, heat shock proteins, etc.)
morphological features of necrosis
- increasingly translucent cytoplasm
- swelling of organelles
- condensation of chromatin into small patches
- increased cell volume leading to disruption of plasma membrane
morphological characteristics of dying cells
- shrinkage
- membrane blebbing
- fragmentation
- nuclear condesnation
why do cells undergo apoptosis
- serious damage that cannot be repaired or requires too much energy to repair
- outlived usefulness (e.g. shutdown of cytotoxic T-cells during immune response occurs via apoptosis)
- become senescent (old)
- necessary to reach final form in embryonic development
- necessary for maintaining normal physiological processes in organism
normal physiological processes maintained by apoptosis
- countebalancing cell proliferation to maintain homeostasis in rapidly reneqing tissues
- mammary gland involution at weaning
- shedding of uterine lining each month in females
- matching number of neurons with targets
role of apoptosis in sculpting tissues
- paw in mouse embryo: interdigital cell death eliminates tissue between developing digits
- as a tadpole becomes a frog all tail cells are deleted
- human embryos are thought to use apoptosis to remove webbing between digits
knockout Bak and Bax gene mice
- Bak and Bax are functionally redundant apoptosis genes
- webbing is not removed and paw does not develop normally
role of apoptosis in neuronal development
in embryo lacking “caspase-9” (key apoptosis gene), there was an overgrowth of the brain due to thickened ventricle walls with no cavitation (hollow space under ventricle wall)
role of apoptosis in neuronal development
in embryo lacking “caspase-9” (key apoptosis gene), there was an overgrowth of the brain due to thickened ventricle walls with no cavitation (hollow space under ventricle wall)
apoptosis in the eye
lens consists of apoptotic cells that repace innards with clear protein crystallin
apoptosis in skin
- skin cells migrate to surface in layers, undergoing apoptosis on the way
- resulting dead cell layer forms the protective outer skin layer, called the epidermis
apoptosis in thymus
T-cells that are ineffective or would attack the body’s own tissues commit suicide before they can enter bloodstream
apoptosis in uterus
cells of the uterine wall die and are sloughed off dring menstruation by apoptosis
apoptosis in other cells
- infected cells (by virus or genetic mutations) often commit suicide
- failure of genetically altered cell to commit suicide can contribute to development of cancer
what is syndactyly
when the cells in the interdigital space fail to undergo apoptosis with the outcome that the foetus will be born with webbed feet and/or hands
how does too little apoptosis contribute to disease
- cancer (establishment, metastasis, treatment failure)
- autoimmune disorders
- viral infection
how does too much apoptosis contribute to disease
- neurodegenerative diseases (alzhimers, parkinsons)
- viral infection (HIV)
- ischemic injury
caspases
- cystine-dependent aspartate-drected proteases
- cleave substrates after an aspartate residue at c-terminal side witbhin an appropriate recognition sequence
- vast number of proteins are cleaved during apoptosis
- cleavage of any one protein probably does not trigger cell death
what could be a reason for “innocent bystander” cleavages in apoptosis
the relatively short cleavage sequence of caspases
how can apoptosis be induced extrinsically
through ligand/receptor interactions (e.g. T-cells inducing targets to commit suicide)
how are initiator caspases activated
- activated by protein:protein interactions
how are effector caspases activated
- activated by proteolytic cleavage
synthesis of caspases
- inactive proenzymes that are processed to form active enzymes
activation of the caspase cascade in apoptosis
- pro-apoptotic signal -> initiator caspase via autocatalytic processing triggered by co-factor binding and/or oligomerisation
- initiator caspase -> effector caspase via processing by initiator caspase
- effector caspase -> death via cleavage of many substrates
extrinsic apoptotic pathway
- death receptor
- FADD
- caspase 8
- caspase 3
- apoptosis
intrinsic apoptotic pathway
- drugs
- cytochrome c
- apaf1
- caspase 9
- caspase 3
- apoptosis
how do initiator caspases get dimerised and activated
- extrinic pathway
- death-receptor mediated apoptotic pathway
activation platform for caspase-8
- DISC (death-inducing signalling complex)
- death receptor and adapter protein FADD -> leads to recruitment of caspase 8 to the complex
extrinsic pathway
what regulates mitochondrial permeabilisation
Bcl-2 family proteins
pro-survival Bcl-2 family members
-BCL-2
- BCL-XL
- BCL-W
- A1/BFL-1
- MCL-1
- BOO
pro-apoptotic Bcl-2 family members
- BAX
- BOK
- BCL-HS
- BAK
- BCL-CL
- BFK
pro-apoptotic Bcl-2 family members (BH3 only)
- PUMA
- BAD
- BIK
- HRK
- BIM
- NOXA
- BMF
how Bcl-2 family members regulate apoptosis and cell survival
- pro-apoptotic act to initiate cytochrome c release
- pro-survival act to inhibit cytochrome c release
regions of anti-apoptotic Bcl-2 proteins
BH4, BH3, BH1, BH2, TM
regions of pro-apoptotic Bcl-2 proteins
BH3, BH1, BH2, TM (or BH3 only)
Bax and Bak activation in MOMP
- ## mitochondrial outer membrane permeabilisation
