apoptosis and cell necrosis
TRANSCRIPT
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Apoptosis and Cell
Necrosis
Group 5
Mallare, Melvin
Manabat, Armand Jeric
Manalang, Kerwin
Manalili, Maria Minerva
Manarang, Grace Haziel
Mancia, Chester
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APOPTOSIS
programmed cell death
is a normal component of the
development and health of multicellular
organisms.
is a process in which cells play an active
role in their own death.
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Biochemical events lead to characteristic cellchanges (morphology) and death.
blebbing loss ofcell membrane asymmetry and
attachment
cell shrinkage
nuclearfragmentation
chromatin condensation
chromosomalDNA fragmentation.
http://en.wikipedia.org/wiki/Biochemicalhttp://en.wikipedia.org/wiki/Morphology_(biology)http://en.wikipedia.org/wiki/Bleb_(cell_biology)http://en.wikipedia.org/wiki/Cell_membranehttp://en.wikipedia.org/wiki/Cell_nucleushttp://en.wikipedia.org/wiki/Chromatin_condensationhttp://en.wikipedia.org/wiki/Chromosomehttp://en.wikipedia.org/wiki/DNAhttp://en.wikipedia.org/wiki/DNAhttp://en.wikipedia.org/wiki/Chromosomehttp://en.wikipedia.org/wiki/Chromatin_condensationhttp://en.wikipedia.org/wiki/Cell_nucleushttp://en.wikipedia.org/wiki/Cell_membranehttp://en.wikipedia.org/wiki/Bleb_(cell_biology)http://en.wikipedia.org/wiki/Morphology_(biology)http://en.wikipedia.org/wiki/Biochemical -
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(A). Typically, the cell begins to shrink
following the cleavage of lamins and actin
filaments in the cytoskeleton
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(B). The breakdown of chromatin in thenucleus often leads to nuclear
condensation and in many cases the
nuclei of apoptotic cells take on a "horse-
shoe" like appearance
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(C) Cells continue to shrink
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The end stages of apoptosis are often
characterized by the appearance of
membrane blebs (D) or blisters process.
Small vesicles called apoptotic bodies arealso sometimes observed
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There are a number of mechanisms
through which apoptosis can be induced in
cells. The sensitivity of cells to any ofthese stimuli can vary depending on a
number of factors such as the expression
of pro- and anti-apoptotic proteins .
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This prevents nearby phagocytes from
locating and engulfing the dead cells
caused by external factors, such as
infection, toxins or trauma.
http://en.wikipedia.org/wiki/Phagocytehttp://en.wikipedia.org/wiki/Phagocyte -
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APOPTOSIS NECROSIS
NATURAL YES NO
EFFECTS BENEFICIAL DETRIMENTAL
Physiological or
pathological
Always pathological
Single cells Sheets of cells
Energy dependent
Energy independent
Cell shrinkage Cell swelling
Membrane integrity
maintained
Membrane integrity lost
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APOPTOSIS NECROSIS
Role for mitochondria and cytochrome
C
No role for mitochondria
No leak of lysosomal enzymes Leak of lysosomal enzymes
Characteristic nuclear changes Nuclei lost
Apoptotic bodies form Do not form
DNA cleavage No DNA cleavage
Activation of specific proteases No activation
Regulatable process Not regulated
Evolutionarily conserved Not conserved
Dead cells ingested by neighbouring
cells
Dead cells ingested by neutrophils and
macrophages
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Internal Mechanism
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Caspases
Caspases are cysteine proteases that
cleave peptide bonds next to an aspartate
residue.
Types:
1. Initiator Caspases - cleave other procaspases
2. Execution Caspases - cleave other cellular
proteins involved in maintaining cellular integrity
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Intracellular signalsOxidative damage from free radicals, Radiation, Virus infection, Nutrient deprivation,
Pro-apoptotic Factors
Damage to the mitochondrial membrane increasing permeability
Entry of Cytochrome C into the cytoplasm
Cytochrome C binds to Apaf-1 forming an apoptosome
Apoptosome activates procaspase-9 to caspase-9
Caspase-9 cleaves and activates caspase-3 and caspase-7.
This executioner caspases activate a cascade of proteolytic activity that leads to:
Chromatin condensation, DNA fragmentation, Protein cleavage, Membrane
permeability
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External Mechanism
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Apoptosis triggered by external signals: theextrinsic or death receptor pathway
Fas and the TNF receptor are integralmembrane proteins with their receptor domains
exposed at the surface of the cell
binding of the complementary deathactivator (FasL and TNF respectively) transmitsa signal to the cytoplasm that leads to
activation ofcaspase 8 caspase 8 initiates a cascade of caspase
activation leading to
phagocytosis of the cell or apoptosis.
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Example : When cytotoxic T cells recognizeor bind to their target,they produce
more FasL at their surface.This binds with the Fas on the surface of the
target cell leading to its death by apoptosis.
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Role of Apoptosis
Why should a cell commit suicide? There are two different reasons.
1. Programmed cell death is as needed for proper developmentas mitosis is.
Example: The resorption of the tadpole tail at the time of its metamorphosis
into a frog occurs by apoptosis.
The formation of the fingers and toes of the fetus requires theremoval, by apoptosis, of the tissue between them.
The sloughing off of the inner lining of the uterus (the endometrium)
at the start of menstruation occurs by apoptosis. The formation of the proper connections (synapses) between
neurons in the brain requires that surplus cells be eliminated byapoptosis
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Role of Apoptosis
In Embryogenesis The development and maintenance of multicellular
biological systems depends on a sophisticated
interplay between the cells forming the organism, itsometimes even seems to involve an altruisticbehavior of individual cells in favour of theorganisms as a whole. During development manycells are produced in excess which eventually
undergo programmed cell death and therebycontribute to sculpturing many organs and tissues[Meier, 2000]
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Role of Apoptosis
In Development and Differentiation of Tissues an integral part of both plant and metazoan
(multicellular animals) tissue development
does not resemble the sort of reaction that comes asa result of tissue damage due to accident orpathogenic infection (cell death by necrosis). swelling and bursting - hence spilling their possibly damaging
internal contents into extracellular space
apoptotic cells and their nuclei shrink, and oftenfragment. In this way, they can be efficientlyphagocytosed (and, as a consequence of this, theircomponents reused) by macrophages or byneighboring cells.
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Role of Apoptosis
2. Programmed cell death is needed todestroy cells that represent a threat to
the integrity of the organism.
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Role of Apoptosis
Apoptosis and AIDS
hallmark- the decline in the number of the
patient's CD4+ T cells (normally about 1000per microliter (l) of blood)
responsible, directly or indirectly (as helper
cells), for all immune responses
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In Cancer
Virus associated cancer
Several human papilloma viruses(HPV) have beenimplicated in causing cervical cancer. One of them
produces a protein (E6) that binds and inactivates the
apoptosis promoterp53.
Epstein-Barr Virus (EBV), the cause of mononucleosisand associated with some lymphomas
produces a protein similar to Bcl-2
produces another protein that causes the cell to
increase its own production of Bcl-2. Both these
actions make the cell more resistant to apoptosis
(thus enabling a cancer cell to continue to proliferate).
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T/TumorSuppressorGenes.htmlhttp://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T/TumorSuppressorGenes.htmlhttp://users.rcn.com/jkimball.ma.ultranet/BiologyPages/B/BurkittLymphoma.htmlhttp://users.rcn.com/jkimball.ma.ultranet/BiologyPages/B/BurkittLymphoma.htmlhttp://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T/TumorSuppressorGenes.htmlhttp://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T/TumorSuppressorGenes.html -
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Some B-cell leukemias and lymphomas express highlevels ofBcl-2, thus blocking apoptotic signals they mayreceive. The high levels result from a translocation of the
BCL-2gene into an enhancer region for antibodyproduction.
Melanoma (the most dangerous type of skin cancer)cells avoid apoptosis by inhibiting the expression of the
gene encoding Apaf-1. Other cancer cells express high levels ofFasL, and can
kill any cytotoxic T cells (CTL) that try to kill them
because CTL also express Fas (but are protected from
their own FasL). Some cancer cells, especially lung and colon cancer
cells, secrete elevated levels of a soluble "decoy"
molecule that binds to FasL, plugging it up so it cannot
bind Fas. Thus, cytotoxic T cells (CTL) cannot kill thecancer cells
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In Immune system
The immune response to a foreign invader involves the
proliferation of lymphocytes T and/or B cells. When their
job is done, they must be removed leaving only a small
population of memory cells. This is done by apoptosis.
Very rarely humans are encountered with genetic defects inapoptosis. The most common one is a mutation in the gene
for Fas, but mutations in the gene for FasL or even one of
the caspases are occasionally seen. In all cases, the
genetic problem produces autoimmunelymphoproliferative syndrome or ALPS.
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Features: an accumulation of lymphocytes in the lymph nodes
and spleen greatly enlarging them.
the appearance of clones that are autoreactive; that is, attack"self" components producing such autoimmune disorders as
- hemolytic anemia
- thrombocytopenia
the appearance oflymphoma a cancerous clone oflymphocytes.
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Determination of cells undergoing
apoptosis
http://www.pnas.org/content/94/19/10385/F2.large.jpg
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I. Cytomorphological alterations
II. DNA fragmentation and micronuclei formation
III.Externalization of membrane
Phosphatidylserine
IV.Activation and presence of caspases,
cleaved substrates regulators and inhibitors
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Externalization of
Phosphatidylserine of the inner cell
membrane Cells that undergo PCD display an eat
me signals to elicit phagocytosis
The signal is Phosphatidylserine (PS) ofthe inner leaflet of the cell membrane
Apoptotic cell flips the PS to the outside
leaflet to let the phagocytic scavengersrecognize the signal
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This signaling of dying cells let the
scavenger cells phagocytose without
eliciting any inflammatory response
The lack of this PS receptors can lead to
the accumulation of undigested cells thathave undergone apoptosis
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DNA fragmentation & micronuclei
formation
Fragmentation of the chromatin result in
degradation of the nucleus and theformation of nuclear blebbing
Nucleic acid staining by the use of
fluorescent dyes can reveal micronucleibodies that are inherent to apoptotic cells
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Nuclear fragmentation and
micronuclei formation
http://physiologyonline.physiology.org/content/19/3/124/F2.large.jpg http://www.cancerquest.org/images/apo
ptosis.gif
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DNAfragmentation
Chromatin materials
condensed and
show a ladder
pattern of lowmolecular weight
DNA fragments
when
electrophoresis
technique is used.
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Cytomorphological alterations
Cytoskeleton degradation and asymmetry
of the cell membrane
Change in the permeability of the cell
membrane
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Degradation of cytoskeleton
Caspases digest the cytoskeletal proteins
of the apoptotic cells
This leads to the asymmetry of the cellmembrane
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Change in membrane
permeabilityApoptotic cells have different membrane
permeability than normal cells
Determination of possible apoptotic cells isthrough the use of stains (can either be
fluorescent or not) that take advantage of
this change in permeability Stains able to label the apoptosome with
the dye
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Detection and presence of
Caspase Caspase are cysteine-aspartic acid
specific proteases that mediates the
events that are associated withprogrammed cell death
Caspase-3 key effector in the apoptosis pathway, amplifying the signal
from initiator caspases and signifying full commitment to
cellular disassembly
Caspase-8 acts as an initiator of the caspase activation cascade