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 SABiosciences' 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 SABiosciences' apoptosis PCR arrays and other technologies.