cell death - wordpress.com · 2016-12-22 · • necrosis is a pathological process induced by...
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CELL DEATH
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Cells die by one of TWO
mechanisms:
Necrosis or Apoptosis
OVERVIEW:
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• Necrosis is a pathological process induced by accidental cell damage.
• A number of toxic chemical or physical events can cause necrosis: toxins,
radiation, heat, trauma, lack of oxygen due the blockage of
blood flow, etc.
• As necrotic cells begin to die, they swell (increase in size), holes
appear in the plasma membrane and intracellular materials
spill out into the surrounding tissue inducing an inflammatory
response to the neighbor cells.
• It is completed within several days
E.g. Gangrene : a type of necrosis caused by insufficient blood
supply. It may occur after an injury or infection, or in people suffering
from any chronic health problem affecting blood circulation (Diabetes
and long-term smoking increase the risk of suffering from gangrene).
Necrosis/morphological features
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Apoptosis/ morphological features
• Apoptosis is a normal physiological process
(non-pathological) that removes “unwanted” cells
without damaging neighboring cells (cellular
contents are not released) and inflammation
does not occur.
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• Apoptotic cells shrinks in size but do not lyse, their plasma
membrane remain intact, part of it bud off (bleb), became
asymmetrical, loss attachment with neighbor tissue.
• Its chromatin condenses,
• the cell fragmented into membrane enclosed structures called
apoptotic bodies which contain: cytosol, condensed chromatin
and organelles
• During apoptosis, a Phosphatidylserine,
(phospholipid) in the inner leaflet of lipid
bilayer, actively held facing cytoplasm by the
enzyme flippase, will invert by scramblase
(floppase) and became exposed on cell surface
using ATP.
• When the phosphatidylserines flip to the
extracellular surface, they act as a signal for
phagocytes cells (e.g. macrophages) to engulf
and degrade the cells (reducing the risk of
inflammation)
• Phagocytes cells also release cytokines (IL-10)
and transforming growth factor (TGF-b) that
inhibit inflammation.
• Apoptosis completes within few hours
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• Effect is beneficial
• Causes can be physiologic or pathologic
• Cellular condensation
• Membranes remain intact
• Requires ATP
• Cell is phagocytosed, no tissue reaction
• In vivo, individual cells appear affected
• Effect is detrimental
• Causes always pathologic
• Cellular swelling
• Membranes are broken
• ATP is depleted
• Cell lyses, eliciting an inflammatory reaction
• In vivo, whole areas of the tissue are affected
Necrosis Apoptosis
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Causes of apoptosis
Physiologic
Pathologic
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Physiologic apoptosis - it’s essential for the proper development and to maintain homeosasis for the
organism:
Apoptosis is used during development of the embryo: There is an extensive cell division during that period leading to an excess of cells that must be removed for normal development and function
* (e.g., in developing nervous system approx. half of the generated nerve cells are immediately undergo apoptosis).
Selective apoptosis sculpt the developing tissues (e.g., Tissues between developing digits, must occur to have separated fingers and toes; incomplete apoptosis can result in abnormal structures)
Homeostasis: In normal adults, the number of cells kept constant by balance between cell division and cell death: If equilibrium is disturbed, abnormal growth (tumors) or loss of cells will occur
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Apoptosis in Pathologic conditions
• DNA damage due to radiation, chemotherapy. • Accumulation of misfolded proteins leads to ER stress which ends with apoptosis. • Viral infections that induce apoptosis such as HIV and Adenovirus or • by the host immune response such as hepatitis.
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Mechanisms of Apoptosis
Activation of caspases
INTRINSIC
(Mitochondrial pathway)
Involves release of cytochrome c (and other proteins) from mitochondria
EXTRINSIC
(Death receptor pathway)
Activated by the engagement of death receptors on cell surface
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Death Receptors
• Belong to tumor necrosis factor receptor (TNFR) superfamily
• Can initiate apoptosis from external signals.
• Only the receptors that have cytoplasmic sequence known as
death domain (DD) can initiate apoptosis (NOT ALL THE
MEMEBERS CAN INITIATE CELL DEATH)
• Adaptor molecules such as FADD (Fas-associated death
domain) and TRADD (TNFR-associated protein) contain such
Death Domains:They interact with the death receptor to
transmit the apoptotic signal to the death machinery via
activation of caspases.
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Exemple of Death receptor:
Fas death receptors
• The Fas death receptor is a member of TNFR
superfamily, initiate apoptotic cell death when it
interacts with Fas ligand (FasL, CD178)
• FasL is expressed in T-cytotoxic cells, NK cells, and
mature B cells as well as in sites of immune
privilege such as the eye, thyroid, lung, brain,
placenta, and testis
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Caspases family
(cysteine-aspartic proteases)
• Cysteine proteases (degrade proteins) that cleave after an Asp residue in their substrate.
• Synthesized as pro-enzymes (inactive) and
then activated when needed (post-translational
modification)
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CARD= caspase-recruitment domain DED= death effector domain L= large catalytic subunit S= small catalytic subunit
• About 11 members in human
• Classified based on function
• Some not involved in apoptosis like:
- Caspases 1& 4 & 5 involved in inflammation
- Caspase 14 important in skin development
The remaining caspases are
involved in apoptosis, grouped
into either initiators or effectors
caspases
Classification of caspases
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Initiator caspases
• Trigger onset of apoptosis by activating the caspases cascade
• Include Caspase 2, 8, 9 & 10.
• These caspases have characteristic region or domains that enable them to
interact with their substrates (effector caspases) and activate them
CARD domain (caspase recruitment domain) in caspase 2 & 9
and
DED domain (death effector domain) in caspase 8 & 10
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are executioner caspases: they undertake the
actual work of destroying critical components
of cell
are: 3, 6 & 7,
Effector caspases
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•FasL interacts with Fas-death receptor
causes trimerization of the Fas receptor
in host cells (infected with virus).
•This result in the clustering of the
receptors DD which then recruit the
cytosolic adaptor protein FADD by
binding FADD death domain.
•FADD contain another domain called
death effector domain that bind to a
domain in pro-caspase 8:
•The complex:
Fas receptor trimer+FADD+caspase 8
is called Death Inducing Signaling
Complex (DISC).
•Upon recruitement procaspase 8
activate itself and caspase 8 then
activates other caspase downstream
such as caspase 3 and 7 that mediate
Extrinsic (Death receptor initiated) pathway
cell killing.
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Intrinsic-Mitochondrial pathway
•Initiates by signal within the cell
•Key protagonists:
- Cytochrome C
- Bcl-2 family members
- APAF-1 (apoptotic protease-activating factor 1)
• Cytochrome is released from the mitochondria as the membrane become permeable and associates with APAF-1 constituting the apoptosome (the “wheel of death”). This structure binds to procaspase-9 promoting its activation (see picture in the next slide)
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The cyt c activates Apaf-1, adaptor protein, which in turn activates caspase 9, of the caspase
proteolytic cascade, that will destroy cell proteins and DNA to cause cell death by apoptosis.
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Bcl-2 family proteins
• Bcl-2 family members directly regulate the release of cytochrome c. • This family contains both pro- and anti-apoptotic proteins. - ANTI-APOPTOTIC: Bcl-2; Bcl-XL; Bcl-W; A1; Mcl-1 - PRO-APOPTOTIC: Bax family (Bax; Bak; Bok); BH3-only family (Bid; Bim, Bik, Bad, Bmf, Hrk, Noxa; Puma) The level between pro- and anti- apoptotic proteins determines if cytochrome c is released from the mitochondrion: IMBALANCE initiates the
death pathway!
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Expression of anti-apoptotic proteins (Bcl-2 over-expression in follicular B-cell lymphoma; over-expression of IAPs in different types of cancers including neuroblastoma)
Inactivation of pro-apoptotic genes (BAX mutation; APAF-1 in melanomas)
Alteration of p53 pathway (p53 mutation)
Altered survival signalling
Deregulation of apoptosis/ Cancer
• Accelerated cell death is found in degenerative diseases and immunodeficiency
• Insufficient apoptosis found in cancer or autoimmunity
• Tumour cells can acquire resistance to apoptosis by :
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-Normal p53 binds p53-response
elements within gene promoter of
protein Bax (pro-apoptotic protein),
triggering apoptosis.
-Mutant p53 can not produce Bax
protein and the cell continues to survive
and divide.
DNA Damage
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Alteration Mechanism of anti-apoptotic
action Types of tumors
CASP3 repression Inactivation of executioner caspase Breast carcinomas
p53 mutation Loss of ability to induce pro-apoptotic genes
Many types
NF-kB constitutive activation Induction of anti-apoptotic genes Many types
Mdm2 over-expression Suppression of p53 levels Sarcomas
APAF-1 methylation Loss of proacaspase-9 activation by Cytochrome c
Melanomas
BAX mutation Loss of pro-apoptotic protein Colon carcinomas
Bcl-2 over-expression Closes mitochondrial channels ~ 50% of human tumours
Akt/PKB activation Phosphorylation and inactivation of pro-apoptotic Bcl2-like proteins
Many types
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Caspase cascade
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END!