Apoptosis (programmed cell death) and necrosis are the two major types of
cell death. Autophagy, which has been proposed as a third mode of cell death, is
a process in which cells digest their own organelles and macromolecules.
Apoptosis, autophagy, and necrosis can all be initiated or modulated by
programmed control mechanisms. RT² Profiler Apoptosis, Autophagy PCR arrays, and
other molecular and biology assays from QIAGEN are widely used in the
research of apoptosis, autophagy, and necrosis. See details here.
The process of apoptosis is triggered by a diverse range of cellular signals.
Either the extrinsic or intrinsic pathways can lead to apoptosis. Extracellular
signals include toxins, hormones, growth factors, cytokines, or nitric oxide.
Heat, radiation, nutrient deprivation, viral infection, hypoxia, the binding of
nuclear receptors by glucocorticoids, or increased intracellular calcium
concentration can damage DNA or cause cellular stress, triggering the release of
intracellular apoptotic signals.
Two distinct but convergent pathways can initiate apoptotic responses: the
death receptors and mitochondrial pathways. The death-receptor pathway is
activated when death ligands - TRAIL (TNF-Related Apoptosis-Inducing Ligand),
FasL (Fas Ligand), and TNFalpha (Tumor Necrosis Factor alpha) bind to cell
surface death receptors - members of the TNFR (TNF Receptor) family. TNFalpha is
a cytokine produced primarily by activated macrophages and is the major
extrinsic mediator of apoptosis. Ligation of these receptors causes the
downstream activation of caspase 8. For example, the binding of TNFalpha to
TNF-R1 leads to caspase activation through TRADD (TNF receptor-associated death
domain) or FADD (Fas-associated death domain protein). The interaction between
FasL and Fas results in the formation of the death-inducing signaling complex
(DISC), which contains FADD, caspase 8, and caspase 10. To study more about TNF
and TNFR superfamily, please use QIAGEN's Tumor Necrosis Factors and
Receptors PCR array.
In some types of cells (type I), processed caspase 8 directly activates other
members of the caspase family and triggers the execution of apoptosis. In other
types of cells (type II), the Fas-DISC starts a feedback loop that reinforces
the increasing release of pro-apoptotic factors from mitochondria and the
amplified activation of caspase 8. Cleavage of cytoskeletal proteins by
proteases - which collapses subcellular components, chromatin condensation,
nuclear fragmentation, and the formation of plasma-membrane blebs are the key
morphologic features of apoptosis.
Following death receptor activation in mammalian cells, a balance between
pro-apoptotic (BAX, BID, BIM, PUMA, BAK, or BAD) and anti-apoptotic (Bcl-XL,
Bcl-2, BCLW, MCL1, A1, or BOO/DIVA) proteins of the Bcl-2 family is established.
Interplay between pro-apoptotic and anti-apoptotic members of the BCL2 family
controls the mitochondrial apoptosis pathway. In addition to its essential role
as the cell's energy factory, the mitochondria is also the repository of
apoptosis-inducing, as well as, apoptosis-regulatory proteins. Caspase 9
regulates the mitochondrial pathway. Initiators of this pathway include
increased intracellular ROS (Reactive Oxygen Species) which can lead to
oxidative stress, DNA damage, unfolded protein response, or deprivation of
growth factors. These initiators ultimately lead to increased mitochondrial
permeability, thereby facilitating the release of pro-apoptotic proteins (e.g.,
cytochrome c, which ultimately results in the activation of caspase 9 through
the apoptosome) from the inter-mitochondrial membrane space into the cytosol.
Another of these proteins, SMAC/DIABLO (Second Mitochondria-Derived Activator of
Caspase), antagonizes cytosolic IAP (Inhibitors of Apoptosis Proteins), thus
allowing the activation of caspases and progression of apoptosis.
Activated caspase 8 (death receptor pathway) and caspase 9 (mitochondrial
pathway) in turn mobilize caspases 3 (the key executioner caspase), 6, and 7,
proteases that cause demolition of the cell by cleaving numerous proteins and
activating DNases. The regulation of pro-apoptotic proteins under non-apoptotic
conditions is incompletely understood. It has been found that a mitochondrial
outer-membrane protein, VDAC2, interacts with BAK to keep this
potentially-lethal apoptotic effector under control.
Besides caspase pathways, a caspase-independent apoptotic pathway that is
mediated by AIF (Apoptosis-Inducing Factor) also exists. AIF is a mitochondrial
inter-membrane protein that, after apoptosis induction, can translocate to the
nucleus and cause chromatin condensation and DNA fragmentation in response to
poly-(ADP-ribose)polymerase-1 (PARP-1) activation.
Defective apoptotic machinery has been intensively studied in cancer. The tumor
suppressor gene p53 is a sensor of cellular stress and is a critical activator
of the intrinsic pathway. p53 prevents DNA replication by halting the cell cycle
at G1 when DNA is damaged. Any disruption to the p53 pathway can result in
impaired apoptosis and the possible formation of tumors. Aberrant apoptosis is
also the major cause of many immune diseases (including type I diabetes), neuro-degenerative
diseases, infectious diseases such as hepatitis, cardiovascular diseases, and
sepsis.
Necrosis is characterized morphologically by vacuolation of the cytoplasm,
breakdown of the plasma membrane and an induction of inflammation around the
dying cell attributable to the release of cellular contents and pro-inflammatory
molecules. Cells that die by necrosis frequently exhibit changes in nuclear
morphology but not the organized chromatin condensation and fragmentation of DNA
into 200 bp fragments that is characteristic of apoptotic cell death. It has
become increasingly clear that necrosis and apoptosis share biochemical network.
The final form of a cell's death is highly dependent on its physiologic context
at the time when the death signal is received. Linking the term
"programmed" to the word "necrosis" implies that cellular
signaling pathways initiate necrosis in response to specific cues rather than
"by accident". Programmed necrosis may not simply be a backup when
apoptosis fails, but has a biological function under conditions where an immune
reaction to the dying cell is desirable, such as in microbial infection.
Autophagy is a strategy for survival. Autophagy allows a starving cell or a
cell that is deprived of growth factors to survive. Cells enduring poor
conditions for long will ultimately consume themselves and die. Autophagy occurs
in both the presence and absence of apoptosis. Though very little is known about
this form of cell death, evidence shows that cross-talk among apoptosis,
necrosis and autophagy can occur at multiple levels. For example, lysosomes
proteases, in particular the cysteine cathepsins and the aspartic protease
cathepsin D, are involved in the terminal steps of autophagy and they also play
important roles in the progression of apoptosis.
Apoptosis, necrosis and autophagy have all been shown to be regulated at both
protein and mRNA level. You can study the gene expression changes associated
with apoptotic machinery, necrosis and autophagy processes using QIAGEN's apoptosis PCR arrays and other technologies.
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