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WHAT IS APOPTOSIS ?
+ It is a form of programmed cell death that occurs in
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+ Biochemical events lead to characteristic cell changes
and death.
+ These changes include blebbing, cell shrinkage, nuclear
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DNA fragmentation.
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APOPTOSIS کارا
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ADVANTAGES
* In contrast to necrosis, which is a form of traumatic cell
death that results from acute cellular injury, apoptosis is
a highly regulated and controlled process that confers
advantages during an organism's lifecycle.
+ For example, the separation of fingers and toes ina
developing human embryo occurs because cells between
the digits undergo apoptosis.
+ Unlike necrosis, apoptosis produces cell fragments
called apoptotic bodies that phagocytic cells are able to
engulf and remove before the contents of the cell can
spill out onto surrounding cells and cause damage to
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ACTIVATION MECHANISMS
The initiation of apoptosis is tightly regulated by activation
mechanisms, because once apoptosis has begun, it inevitably leads
to the death of the cell.
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pathway (also called the mitochondrial pathway) and the extrinsic
(3۷
The intrinsic pathway is activated by intracellular signals generated
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the intermembrane space of mitochondria.
BUM adel re وصنصنه عصهونا دابا هه ها هه ور
to cell-surface death receptors, which leads to the formation of the
death-inducina sianalina complex (DISC).
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80۱-2 ۷
The Bcl-2 family proteins consists of members that either promote or
inhibit apoptosis, and control apoptosis by governing mitochondrial outer
membrane permeabilization (MOMP), which is a key step in the intrinsic
pathway of apoptosis.
a tett ان
BH3-only family ( Bim, Bid, Bal, BAD, Bcl-x(S) ) *
*Anti-apoptotic:
Bcl-2 , Bcl-x(L) *
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INTRINSIC PATHWAY
Retin
+ irreparable genetic damage
+ hypoxia
٠ extremely high concentrations of cytosolic Ca+
٠١ severe oxidative stress (O,- , OH , H,O, )
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تا
“They may cause mitochondrial swelling through the formation of membrane
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and cause apoptotic effectors to leak out.
Cytochrome c will release from mitochondria. Once cytochrome c is released
it binds with Apoptotic protease activating factor - 1 (Apaf-1) and ATP, which
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of caspase-9, which in turn activates the effector caspase-3.
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cytosol. SMAC binds to proteins that inhibit apoptosis (|APs) thereby
deactivating them, and preventing the IAPs from arresting the process and
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INTRINSIC PATHWAY OF APOPTOSIS
(Mitochondria Mediated Programmed Cell Death Pathway)
Mitochondria
Severe DNA Damage ۰ ۳
0
Activation of Pro-
Apoptotic Factors
تج تس |
Mitochondrial membrane
a” arorrososg,
۷ >
Inhibition of Anti 2
apoptotic Factors 2
fProcaspase 9
سک
Activation of Caspase-3 by Caspase-9
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EXTRINSIC PATHWAY
* The extrinsic apoptotic pathway (death receptor-
dependent) is initiated by the interaction of cell surface
exposed death receptors, belonging to the superfamily
of tumor necrosis factor receptor (7))""), with their
respective protein TNF family ligands.
TNF-alpha is the major extrinsic mediator of apoptosis.
Most cells in the human body have receptors for TNF-
alpha. The binding of TNF-alpha to TNFR has been shown
to initiate the pathway that leads to caspase activation
via the intermediate membrane proteins TNF receptor-
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Intrinsic pathway
aD | pro-caspase-10
Caspase-8 and
caspase-10—>
BID
‘Apopt
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MORPHOLOGICAL CHANGES
>Cell shrinkage and rounding occur because of the
retraction and the breakdown of the cytoskeleton by
caspases.
>The cytoplasm appears dense, and the organelles appear
tightly packed.
»Chromatin undergoes condensation into compact
patches against the nuclear envelope in a process known
as pyknosis, a hallmark of apoptosis.
>The nuclear envelope becomes discontinuous and the
DNA inside it is fragmented in a process referred to as
karyorrhexis. The nucleus breaks into several discrete
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KARYOLYSIS PYKNOSIS KARYORRHEXIS.
Nuclear fading Nuclear shrinkage Nuclear fragmentation
Nuclear dissolution
ANUCLEAR NECROTIC CELL
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REMOVAL OF DEAD CELLS
٠ Dying cells that undergo the final stages of apoptosis
display phagocytotic molecules, such as
phosphatidylserine, on their cell surface.
* Phosphatidylserine is normally found on the inner surface
of the plasma membrane, but is redistributed during
apoptosis to the extracellular surface by a protein known
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٠ These molecules mark the cell for phagocytosis by cells
possessing the appropriate receptors, such as
macrophages.
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THE END