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Apoptosis summary
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Summary of all lectures master course Apopotis: NWI-BM004C
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Week 1 – ApoptosisOverall concept: Cells detach from surrounding > cell changes morphology (becomes smaller, denser,
forms apoptotic bodies) > macrophages will phagocytose the apoptotic bodies.
Reason why it took so long before studying apoptosis:
1) researchers not interested in a dead cell
2) difficult: because dead cell is just junk. The trick was: C.elegans. The organism stayed alive while
there were dead cells in the body. Necrosis = cells just die. They swell because of osmotic pressure.
But they saw that dying cells became smaller (this should cost energy) = named apoptosis. When cells
die of apoptosis, they have a specific DNA pattern. Similarity between the apoptotic genes and tumor
genes: tumor cells can’t die.
Programmed cell death: cell dies at a certain place at a certain position. It is genetically determined.
Genetic pathway for programmed cell death in C.elegans:
When a healthy cell is committed to die, the dead cell is engulfed by another cell. They have defined
genes which are needed for degradation, engulfment and genes which are involved in apoptotic
process.
Ces-2 = inhibitor of ces-1 (present in healthy cells)
Ced-9 = inhibitor (kept cells alive)
egl-1 = activators (inhibitors Ced-9, activated ced-3 & ced-4)
Experiment performed: Loss-of function screening: irradiated worms, mutated genes. Take the
worms, look under microscope and count the cells.
Similarities between pathways to cell death in C.elegans and mammals
Comparison of the C. elegans CED protein pathway and the core apoptotic machinery in mammalian
cells shows conservation of the general outline of the pathway.
Types of cell death
Apoptosis = means ‘falling leaves’ is controlled from of cell death
Necrosis = uncontrolled form of cell death (passive form of cell death)
Programmed cell death = genetically encoded cell death
Anoikis = programmed cell death that is induced in anchorage-dependent cells when they detach
from the surrounding extracellular matrix
Autophagic cell death = dying cells displaying a large-scale accumulation of autophagosomes.
Autophagy is considered to be a pro-survival pathway in the dying cell. Cells die with autophagy,
rather then by autophagy.
“what researchers said: Cell die in a neat way by apoptosis and not by necrosis.”
1
,Necroptosis = controlled from of necrosis
Pyroptosis = A highly inflammatory form of programmed cell death that occurs most frequently upon
infection with intracellular pathogens and is likely to form part of the antimicrobial response. It is an
intermediate between apoptosis and necrosis, uniquely dependent on caspase-1.
Cells which have taken up a pathogen. The cell tries to get rid of the bacteria, it starts producing
inflammatory factors (induce inflammation). Cells dies by necrosis. Inflammatory way of dying.
Parthanatos = stimulated in response to extreme genomic stress, it is uniquely dependent onPARP-1.
Ferroptosis = related to the antioxidant defense system. Programmed cell death caused by iron-
dependent accumulation of lipid peroxides. Iron induces ROS.
Mitotic catastrophe = due to premature or inappropriate entry of cells into mitosis leading to
programmed cell death, often induced by radiation, chemotherapeutic drugs or hyperthermia.
NETosis = A pathogen-induced cell death of neutrophils, thereby excreting their DNA leading to
neutrophil extracellular traps (NETs) able to catch and kill extracellular pathogens.
Summary:
Function of programmed cell death in animal development
-Sculpting (skin in between fingers is degraded in humans)
-Deleting unwanted structures (frog tail, during development organs female/male removed)
-Controlling cell numbers (cells not attached to each other, no survival signal, they die)
-Eliminating nonfunctional, harmful, abnormal or misplaced cells. (T-cells auto reactive, tumor cells)
A dead cell still has a function, specialized cell death: e.g. skin cells for cornification, platelets for
blood coagulation, lens cells for transparency, red blood cells for oxygen transport.
Stressed cells may choose between apoptosis and senescence
Senescence cell = if a cell get stress, normally the cell dies by apoptosis. But some stresses at some
cells, they don’t die but decide to go into senescence. Cell can’t divide anymore (still metabolic
active). It is doesn’t divide, it can’t form a tumor. But a recent discovery showed: senescence cells
secrete factors which harm the organism (inflammatory factors) and they effects organs. If you have
lots of senescence cells, related to aging. Lots of organs don’t function anymore because of
accumulation of senescence cells.
2
, Death pathways
A cell can die in many ways, depends on the cell type and
the time and type of stress.
Death signal to a cell time dependent. For instance: in
red arrow. The cell may start the apoptotic process (2h).
In the meantime the cell wants to survive; autophagic
process (giving energy to keep the cell alive) apoptosis-
like. Other processes may have started (green) necrosis
for example.
The death pathway is most frequently through apoptosis
(left, red branch), either via caspase-9 activation and a
mitochondrial route or directly via caspase-8 to caspase-
3 as a primary effector caspase. Other pathways exist,
including autophagic (middle, pink branch).
If the cell is severely and acutely injured, so that its
membrane permeability is compromised, it may fail
completely, undergo osmotic rupture, and become
necrotic (far right, black branch). Alternatively, it is
possible that, through the progression of its resorption,
the cell may deplete its energy resources and, though
having commenced an apoptotic or autophagic death, it
may revert to necrosis (bottom, black pathway). This
latter is particularly likely where phagocytosis of the dying cell is compromised, as in massive
toxic death and with cell lines maintained in culture.
Too hot cup of tea: will the cell die of apoptosis or necrosis (by necrosis because no time for
apoptosis).
Cell type dependent
Situation dependent
Type of stress dependent
Apoptosis
Controlled process to efficiently deplete cells without cell lysis
crucial process in development, growth/maintenance/ immune system
Morphology: small condensed nucleus, blobs on the outside, short mitochondria (function remains
intact).
Apoptosis vs necrosis
Stress causes dysfunction of the cell.
Necrosis Apoptosis
loss of membrane integrity, less condense Membrane blobbing, but no loss of integrity
chromatin Aggregation of chromatin
Swelling and lysis Cellular condensation
No vesicle formation, complete lysis Formation of membrane bound vesicles
Disintergration (swelling) of organelles
No-energy requirement ATP dependent
Random late digestion of DNA Early specific DNA fragmentation (separate DNA
3
, on ladder, you see specific bands)
Need an inflammation to occur Induced by physiological stimuli
Evoked by non-pysiological disturbances No inflammatory response
Phagocytosis by macrophages
o Apoptotic process: Three phases
1)Activation phase
Extrinsic pathway
(receptor-mediated) by the
receptor caspase 8 is
activated.
- Death receptor signaling
intrinsic pathway
(cellular stress signal)
-Mitochondrial signaling
pore is opened, activate
Caspase 9
2)Execution phase
-Caspase cascade
3)Burial phase
o TNF family death receptors
Ligand (trimer) induces trimerization of the receptor.
3 types of death receptors:
1)CD95/Fas receptor
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