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Origins of PCD
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Coveres the PCD lecture - extra reading with sources cited
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Voorbeeld van de inhoud
Origins of PCD Why do cells sacrifice themselves (started in single celled organisms)
Levels of selection conflict (viruses/phages vs. bacteria/ retroelements)
What is programmed cell death (PCD)?
PCD = all genetically encoded processes that lead to cell suicide
- Apoptosis is most commonly associated with eukaryotic PCD
- Other mechanisms include autophagic death, programmed necrosis
- All mechanisms require metabolic energy, typically induced in response to
physiological/developmental signals, can be inhibited
Active, genetically regulated cell death process that contributes to
development/functionality of the organism (whether by removing damaged/mutated
cells or in multicellular organisms enables growth of complex of structures
shaping the hand by removing interdigital-web)
Self-destruction of individual cells can be seen as an extreme form of cooperation
that is costly to the lower level (the cell), but benefits the higher level
(multicellular individual)
- The altruistic behaviour is analogous – in terms of the associated loss of direct
fitness – reproductive altruism generally displayed by somatic cells in
multicellular organisms
Process of Apoptosis – eukaryotic cells
Active cell death (PCD requires energy/ATP, genetically determined, can be
inhibited)
Why is apoptosis so complex – driving force, selection pressures?
- Pathways of signal transduction intimidating in complexity
- Metabolic networks give no indication of evolutionary depth – enzymes are simply
nodes on a network
- Have revealing evolutionary history
Caspase cascade
once apoptosis begins – irreversible process, must be tightly regulated
Enzyme cascade amplifies a small signal into a major response – each enzyme
activates multiple target enzymes – each of which repeats the process: exponential
number of enzymes that digest the cell in a systematic way
Amplification via enzyme cascade allows great sensitivity to a signal, but can amplify
false positives a large number of inhibitors, so overall outcome (apoptosis or
survival) depends on balance between activators and inhibitors
Inhibitors equally abundant – Bcl-2 family proteins, heat shock proteins (hsp90,
hsp27, hsp70)
, Mitochondria are central to apoptosis (mitochondrial mediated apoptosis by release
of cyt-c): the reason why apoptosis is so complex may be due to the interplay
between host and endosymbiont in the early evolution of the eukaryotic cell
Extrinsic Pathway
Involves transmembrane death receptors, members of the
tumour necrosis factor (TNF) receptor gene superfamily
TNF (death) receptors bind to extrinsic ligands and transduce
intracellular signals that result in the destruction of the cell
Best known ligands of death receptors = FasL, TNF-1a, Apo3L,
Apo2L
Signal transduction via extrinsic pathway involves caspases 8,
3, 6, 7 – all proteases with specific cellular targets once
activated, caspases affect several cellular functions = death
of cells
Intrinsic Pathway
Always involves mitochondria: non-receptor mediated intracellular signals
Stimuli include: viral infections or damage (eg. to DNA) by toxins, ROS or radiation
Induce loss of mitochondrial membrane potential (hence fall in ATP synthesis) –
release of pro-apoptotic proteins into cytosol (eg. cytochrome c, SMAC/Diablo)
Pro-apoptotic proteins activate caspases which mediate cell death
Regulation through activity of Bcl-2 family and p53; Bcl-2 proteins may be pro- or
anti-apoptotic
- Anti-apoptotic: Bcl-2, Bcl-x, Bcl-xL, Bcl-xs, Bcl-w, BAG
- Pro-apoptotic: Bcl-10, Bax, Bak, Bid, Bad, Bim, Bik, Blk
- Both pathways linked via caspase 8 (which activates BID)
- BID truncated – migrates to mitochondria, leads to release of cytc
Intrinsic and extrinsic pathways are linked through BID
Both pathways linked via caspase 8 (which activates BID)
Full length BID is localised in cytosol (BID = BH3 interacting-domain death agonist)
Truncated BID (tBID) translocates to mitochondria and transduces apoptotic
signals from cytoplasmic membrane to mitochondria
- tBID induces release of cytochrome c, loss of mitochondrial membrane
potential, cell shrinkage and nuclear condensation in a caspase-dependent
fashion
- BID is a mediator of mitochondrial damage induced by Casp8 in the extrinsic
pathway (Li et al., 1998)
Mitochondria therefore involved in both intrinsic and extrinsic pathways
, PCD trends in various organisms
In plants (Balk, 2001): In fungi:
PCD pathway similar to apoptosis found Yeasts and filamentous fungi – similar
Similar stages, overall process and morphological stages (DNA
morphology fragmentation – revealed by TUNEL
Caspases are specific to animals, many staining)
plants and algae have related Mitochondria and ROS involved but
metacaspases metacaspases (as in plants) rather
Metacaspases have caspase-like than caspases
activity, but also have other roles in Cytochrome c release and Bcl2 are
growth and cell cycle (pleiotropic) involved
Cytochrome c release is involved in
plants but NOT all eukaryotes
Unicellular algae In yeasts (particularly):
Prolonged darkness in unicellular In Saccharomyces cerevisiae we see
eukaryotic phytoplankton (Dunaliella conserved:
tertiolecta) induces PCD – as do viral Cytochrome (ctyc1) release, ROS,
infections, light stress, ROS, nitric AIF-1 (apoptosis-inducing factor, non-
oxide, toxins (aldehydes), iron caspase mitochondria-derived death)
depletion (used in FeS proteins and Bax and Bak (Bcl-2 family)
hemes in photosynthesis) (Bidle, 2004)
Vast algal blooms disappear rapidly as In protists
a result of PCD – major effect on Overall conclusion – PCD is probably
marine life carbon cycle ancestral to eukaryotes, involved
Metacaspase-induced cell death, mitochondria, ROS, mitochondrial
resembling apoptosis originated in proteins such as cytochrome c
cyanobacterial blooms – maybe (Lane,
2008)
Conserved characteristics of PCD lead to surprising conclusion: mitochondria play quite
an important role
loss of cytc (and some other mitochondrial proteins), ROS leak, loss of membrane
potential, fall in ATP concentration
- Almost all of these proteins have prokaryotic homologues, as does the caspase
superfamily
- Balanced between pro- and anti-apoptotic Bcl-2 family members (notably Bcl-2
and Bax) controls likelikhood of apoptosis
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