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APOPTOSIS
Programmed Cell Death:
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Apoptosis (Programmed) vs
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Apoptosis is the most commonly described pathway for programmed cell death,
which is cellular suicide resulting from the activation of a dedicated intracellular
program
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Often these cells appear completely healthy prior to committing suicide
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At the other end of the spectrum is necrosis, also called accidental cell death, which
occurs when cell receive a structural or chemical insult that kills them outright, i
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temperature or physical trauma
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The cell itself can also initiate necrosis in response to certain stimuli, particularly
when induction of apoptosis is inhibited
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In contrast to the orderly biochemical pathways of apoptosis, which involve the
action of enzyme cascades and the consumption of ATP, necrosis typically involves a
collapse of normal cell physiology as a result of ATP depletion
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Caused by:
- Severe oxidative stress
- Ischemia
- Hypoxia
- Hypothermia
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• Apoptosis:
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Apoptotic cells shrink rather than swell, as part of a reproducible pattern of
structural alterations of both the nucleus and cytoplasm
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Other morphological characteristics include:
- Chromatin condensation
- Apoptotic body formation
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Overall, it is important to note that cell death is not as black and white as it may
seem
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The C
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A genetic analysis of programmed cell death in the developmental model system C
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Key genes were: ced-9, ced-4, ced-3 and
egl-1
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This family was the first identified mammalian regulator of apoptosis and is part of
the t(14:18) chromosomal translocation, found in a large percentage (~85%) of
human follicular B-cell lymphomas
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When the gene was placed next to a strong promoter of antibody production, there
was an upregulation of the Bcl-2 protein
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In turn, the B cells no longer died under normal physiological conditions, and instead
became immortalised, i
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live for years instead of weeks
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The Bcl-2 gene is defined as a new type of oncogene, in that, instead of undergoing
apoptosis, the cells become immortalised
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elegans apoptosis vs
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In C
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Ced-4 forms a dimer
with ced-3 and this activates ced-3
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Ced-3 is the mammalian equivalent of a caspase, thus becoming an active protease
that can cleave off various protein targets within the cell
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As you can see, there is a fairly linear nature of apoptosis within the C
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The Control Mechanisms:
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The Fas Mediated Apoptosis Pathway:
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There was an evolution from simple, homodimer proteins, to more complex,
heterodimer molecules
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Cytochrome C induces a conformational change in APAF-1, exposing a CARD (caspase
recruitment domain) domains and resulting in oligodimerization into heptamers
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CARD/CARD interactions recruit and dimerize procaspase-9, where the dimerization
and allosteric changes activate the protease
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There are also various inhibitors in this pathway, such as IAP (inhibitor of apoptosis,
such as XIAP which inhibits the activation of caspase-9)
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Additionally, you have inhibitors of the inhibitors such as SMAC, and also inhibitors
of inhibiting inhibitors
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This demonstrates the complex control of this pathway and the importance of
homeostasis
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One important target of caspase-3 is ICAD (inhibitor of CAD), which cleaves CAD
(caspase activated deoxyribonuclease)
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This process begins extracelluarly and ends up in the nucleus where it disrupts the
genome, thus preventing any mutations being passed on
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• Modular nature of information transfer, i
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dimerization of homologous domains
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• Many analogous pathways are used in different cell types at different stages of
development
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Bcl-2 proteins can be grouped into 3 subfamilies:
- Bcl-2 protectors protect cells against apoptosis
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Bcl-2 regulators promote cell killing by either interfering with the protectors or
activating the killers
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These genes are defined by the presence of one to four short blocks of conserved
protein sequences called Bcl-2 homology domains (BH)
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Anti-apoptotic Bcl-2 protectors typically have four of the domains, whilst proapoptotic Bcl-2 killers have 3 of these domains
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The pro-apoptotic Bcl-2 regulators have only the BH3 domain, which is a short
segment of helix that fits into a groove on the surface of both Bcl-2 protectors and
killers, forming a complex that regulates their activity
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Bcl-2 protectors regulate the activity of Bcl-2 killers by forming a complex, thus
interfering with the ability of Bax (a killer) to kill cells
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Apoptosis can be regulated transcriptionally or through post-translation
modifications, which depends on the time requirements of the system
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For example, CTL-mediated destruction of virus infected cells undergoes in minutes
due to the danger this poses to the animal and is thus post-translational
modification, whereas, the loss of tail in tadpole development occur over weeks and
thus transcriptionally regulated
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P53 activates the expression of pro-apoptotic family members, i
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Bax and Bid and
represses the anti-apoptotic family members, i
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Bcl-2 and Bcl-X1
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BH3-only pro-apoptotic Bcl-2 family members are sequestered in the cytoplasm and
can bind to calcium, resulting in a translocation so it can go to the mitochondria and
bind to Bcl-2
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In C
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Caspases:
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Apoptosis in Human Diseases:
• Insufficient Apoptosis:
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• Excessive Apoptosis:
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Neurodegeneration – Alzheimer’s disease, Huntington’s, Parkinson’s
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Type I diabetes – CTL-mediated destruction of beta-islet cells of Langerhans
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Many pathogens seek to take advantage of apoptosis pathways, i
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bacteria
produce apoptosis-inducing virulence properties and viruses encode antiapoptotic molecules to avoid immune cell destruction
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Furthermore, HIV has a number of different mechanisms for inducing apoptosis
of T cells