Apoptosis is programmed cell death that is carried out in a multicellular organism. Apoptosis leads to the production of cell fragments called apoptotic bodies that phagocytic cells engulf and quickly remove.
Apoptosis is designed to carry out functions of the body development. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose, separating the digits.
Between 50 and 70 billion cells die each day due to apoptosis in the average human adult.
Defective apoptotic processes have been implicated in an extensive variety of diseases which include atrophies in case of increased apoptosis and cancer when apoptosis is insufficient.
Pathways of Apoptosis
Pathways That Lead to Cellular Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death. In more specific terms, it includes a series of biochemical events that lead to a variety of morphological changes, including blebbing, changes to the cell membrane such as loss of membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation.
Processes of disposal of cellular debris whose results do not damage the organism differentiate apoptosis from necrosis. Multiple triggers can lead to a cell undergoing apoptosis by one of two major pathways.
Death receptors
Fas (CD95), TNFR1, TRAIL receptors have a homologous intracellular region “death domain.” These death domains bind to adaptor protein (Fas binds to FADD, TNFRI to TRADD). These adaptor proteins can activate the cysteine protease, procaspase 8. This can be inhibited by FLIP or FLICE-inhibitory protein.
The activated caspase 8 activates the executioner caspases which in turn activate an endonuclease called caspase-activated DNase as well as others. These endonucleases cleave DNA causing fragmentation and cell death.
Caspases also activate proteases that act on actin microfilaments leading to blebbing of the membrane.
Mitochondria-cellular stress
As a result of mitochondria cellular stress, Bax, Bak, and/or Bid bind to mitochondria. This displaces Bcl-2 and Bcl-x, which are normally on the outer mitochondrial membrane and inhibit apoptosis. When this happens, cytochrome c is released from the mitochondria. Cytochrome c activates the adaptor protein, APAF-1, which is in the cytosol. APAF-1 activates procaspase-9, which activates caspases 3 and 7 causing apoptosis.
Akt inhibits this pathway.
Many tumors have chronically activated Akt, so the tumor cell doesn’t undergo apoptosis.
Others cytotoxic cells (T and NK cells) inject granzyme B, which activates caspases 3 and 7. DNA damage is detected by p53, resulting in the activation of apoptosis. Defective p53 can be found in some tumors and also synoviocytes in rheumatoid arthritis, perhaps contributing to their proliferation.
Abnormalities in cellular apoptosis can lead to cancer and autoimmune disease. Apoptotic bodies can serve as a source of nuclear autoantigens for autoimmune diseases such as systemic lupus erythematosus.
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