Cell Death Flashcards
What three basic mechanisms cause cell death?
- Necrosis
- Apoptosis
- Autophagic cell death
What is apoptosis?
programmed cell death designed to eliminate unwanted host cells through activation of a co-ordinated series of events, supported by a dedicated set of gene products
What is necrosis?
Most common cause of cell death, occurs after stresses such as ischemia, trauma, chemical injury
What is autophagic cell death?
- Responsible for the degradation of normal proteins involved in cellular remodelling (metamorphosis, ageing, differentiation)
- digest and removes abnormal proteins that could accumulate into toxins or cancer
What are some functions of apoptosis?
- selective process for the deletion of superfluous, infected or transformed cells
- involved in:
- embryogenesis
- metamorphosis
- normal tissue turnover
List some examples of apoptosis
- Cell death in embryonic hand to form individual fingers.
- Apoptosis induced by growth factor deprivation (neuronal death from lack of NGF).
- DNA damage-mediated apoptosis. If DNA is damaged due to radiation or chemo therapeutic agents, p53 (tumour suppressor gene product) accumulates. This arrests the cell cycle enabling the cell repair the damage. If repair process fails, p53 triggers apoptosis.
- Cell death in tumours causing regression.
- Cell death in viral diseases (ie viral hepatitis).
- Cell death induced by cytotoxic T cells (ie. Cellular immune rejection or graft vs. host disease).
- Death of neutrophils during an acute inflammatory response.
- Death of immune cells( both T and B lymphocytes) after depletion of cytokines as well of death of autoreactive T cells in the developing thymus
How is apoptosis induced?
- UV and gamma radiation
- Chemotherapeutic drugs
- Growth factor withdrawal
- Cytokines, e.g. TNFa and TGFb
- Loss of extracellular matrix
What are the 2 types of apoptosis?
Intrinsic and extrinsic
What is involved with intrinsic apoptosis?
- DNA damage – p53-dependent pathway
-Interruption of the cell cycle - Inhibition of protein synthesis
- Viral Infection
- Change in redox state
What is involved with extrinsic apoptosis?
- Withdrawal of growth factors (e.g. IL-3)
- Extracellular signals (e.g. TNF)
- T cell or NK killing
What are caspases?
- Cysteine Aspartate-specific proteases
- Caspases are Cysteine proteases that play a central role in the initiation of apoptosis.
- Most proteases are synthesised as inactive precursors requiring activation (usually partial digestion by another protease).
- Their activation leads to characteristic morphological changes of the cell such as shrinkage, chromatin condensation, DNA fragmentation and plasma membrane blebbing.
Why is apoptosis known as death by a thousand cuts?
- Hundreds of substrates for activated caspases
- Substrates fall into most classes of important genes
Substrates and their functions: - Lamin A and B = nuclear envelope
- PARP = DNA repair
- DNA-PK = DNA repair
- Toposiomerase II = DNA replication
- Raf-1 = Signalling
- Akt/PKB = cell survival
- STAT1 = signalling
- eIF4 = translation
How are initiator caspases activated?
- by induced proximity
- eg in response to receptor dimerisation upon ligand binding
- eg cytochrome c release from mitochondria
What does TNF do?
TNF induces the formation of a death-inducing signalling complex (DISC) which is made up of:
- TNF
- TNFR
- FADD
- procaspase-8
What is cytochrome c?
- mitochondrial matrix protein
- known to be released in response to oxidative stress by a permeability transition
- many inducers of the permeability transition also eventually induce apoptosis. - These processes seem to be related and hence the idea arose that apoptosis is induced in response to rises in cytoplasmic cytochrome c
