Mechanism of Apoptosis

Apoptosis: Apoptosis is a cell death process which occurs during development and
aging of cells. It is also induced by cytotoxic lymphocytes (CTL), anti-cancer drugs,
g- or UV-irradiation, a group of cytokines called death factors, and deprivation of
survival factors. For example, in cancer and leukemia. When apoptosis works
overly well, it kills too many cells and inflicts grave tissue damage. This is the case
in strokes and neurodegenerative disorders such as Alzheimer's, Huntington's, and
Parkinson's diseases. Also known as programmed cell death and cell. suicide.
Cause of Apoptosis: Apoptosis is mediated by proteolytic enzymes called
caspases, which trigger cell death by cleaving specific proteins in the cytoplasm and
nucleus. Caspases exist in all cells as inactive precursors, or procaspases, which are
usually activated by cleavage by other caspases, producing a proteolytic caspase
cascade.

Function of Apoptosis: Viral induction of apoptosis occurs when one or several

cells of a living organism are infected with a virus, leading to cell death. Cell death
in organisms is necessary for the normal development of cells and the cell cycle
maturation. It is also important in maintaining the regular functions and activities of
cells.

Mechanism of Apoptosis: Cell death by apoptosis occurs when a specialised

intracellular signalling pathway is activated and kills the cell. Apoptosis is the most
common way of cells to die in vivo but there are other ways (necrosis has been
defined as cell death that is not apoptosis; necrosis may in some cases indeed be
due to simple physical injuries but there also seems to be at least one signalling
pathway that causes necrosis; pyroptosis is when a cell dies as a consequence of
the activity of caspase-1, a protease involved in the maturation of cytokines;
autophagy has also been linked to cell death. Programmed cell death used to be a
term for cell death especially during development, where a cell has the
predetermined fate to die. The term is now commonly used to describe any cell
death that is the result of intracellular signal transduction (a program) and
therefore especially encompasses apoptosis)

Caspase Activation Mechanism: A diversity of mechanisms exists for activating

initiator caspases, thus setting the wheels of the apoptotic machinery in motion.
However, fundamentally, the biochemical mechanisms appear to be remarkably
similar and can be explained by a single model, known as the induced proximity
model. The induced proximity model is predicated on the empirical observation that
the zymogen forms of unprocessed caspases are not entirely inactive but rather
possess weak protease activity (measured in some cases at 1% of the fully active

enzymes). When brought into close apposition through protein interactions, the
zymogens can trans-process each other, producing the fully active proteases.

Though many pathways for activating caspases may exist, only two have been
elucidated in detail. One of these centers on tumor necrosis factor (TNF) family
receptors, which use caspase activation as a signaling mechanism, thus connecting
ligand binding at the cell surface to apoptosis induction. The other involves the
participation of mitochondria, which release caspase-activating proteins into the
cytosol, thereby triggering apoptosis.The death receptor and mitochondrial
pathways for caspase activation are sometimes referred to as the extrinsic and
intrinsic apoptosis pathways respectively, though this is an oversimplification. Also,
though commonly viewed as separate pathways and capable of functioning
independently, cross-talk can occur between these pathways at multiple levels,
depending on the repertoire of apoptosis-modulating proteins expressed

Extrinsic pathway: The extrinsic pathway is activated by extracellular ligands

binding to cell-surface death receptors, which leads to the formation of the deathinducing signaling complex (DISC). A cell initiates intracellular apoptoticsignaling in
response to a stress, which may bring about cell suicide. In the extrinsic pathway,
ligands such as Fas, tumor necrosis factor (TNF), or tumor necrosis factor-related
apoptosis-inducing (TRAIL) ligand bind to death receptors. This results in the
recruitment of Fas-associated death domain protein (FADD) and activation of
caspase 8. Caspase 8 directly activates caspase 3 and 7. The two pathways interact
via caspase 8-mediated cleavage of Bid.

Intrinsic pathway: Apoptosis is a programmed form of cell death involving the

degradation of cellular constituents by a group of cysteine proteases called
caspases. ... The intrinsicapoptotic pathway is characterized by permeabilisation of
the mitochondria and release of cytochrome c into the cytoplasm.In the intrinsic
pathway, the proapoptotic BH3-only family members activate Bax or Bak, leading to
mitochrondrial outer membrane permeabilization, which drives formation of the
apoptosome, activation of the executioner caspases, 3 and 7, and subsequent
apoptosis. The proapoptotic BH3-only proteins are inhibited via interactions with the
anti-apoptotic Bcl-2 family of proteins. The intrinsic (Bcl-2 inhabitable or mitochondrial) pathway of
apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA
damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the
reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and
inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial
membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin
condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway
are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria.
The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with
sequence conservation clustered in BCL-2 Homology (BH) domains