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Apoptosis
Apoptosis is a form of programmed cell death that eliminates unwanted cells through activation of intracellular gene products. It occurs physiologically during embryogenesis and in adult tissues, and pathologically to remove cells damaged beyond repair. The key events of apoptosis include activation of caspase enzymes, DNA fragmentation, and recognition of dead cells by phagocytes. Apoptosis occurs via intrinsic and extrinsic pathways, both activating executioner caspases that break down nuclear and cellular components, leading to removal of dead cells without inflammation.
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Apoptosis
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- 3. APOPTOSISAPOPTOSIS Apoptosis is aform cell death designed to eliminate un wanted host cells through activation of a co ordinated internally programmed series of events effected by dedicated set of gene products. Apoptosis is a form cell death designed to eliminate un wanted host cells through activation of a co ordinated internally programmed series of events effected by dedicated set of gene products.
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- 7. Apoptosis in physiologicsituations Programmed cell death during embryogenesis
- 8. Apoptosis in physiologicsituations Programmed cell death during adult stage
- 9. Apoptosis in pathologicsituations Apoptosis eliminates cells that are genetically altered or injured beyond repair without eliciting a severe host reaction, thus keeping the damage as contained as possible.
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- 11. Biochemical features ofApoptosisBiochemical features of Apoptosis
- 12. Mechanisms of ApoptosisMechanismsof Apoptosis The fundamental events in apoptosis is the activation of enzymes called CASPASES
- 13. • Activation ofseveral members of cystine family called caspases.can be divided into two groups initiator and executioner. • Initiator include caspases 8 and 9. • Executioners including caspases 3 and 6. • DNA breakdown by calcium and magnesium dependent endonucleases into fragments whose sizes are multiples of 180 units to 200 base pairs.fragments may be visualized by electrophoresis. As DNA ladder. • Dead cells are recognized by phogocytes by the help of phospholipid such as phosphatidylserine from inner leaflet to outer leaflet of membrane.
- 15. • Intrinsic (mitochondrial)pathwayof apoptosis • This pathway is result of increased mitochondrial permeability and release of pro apoptotic molecules into cytoplasm. • Release of mitochondrial proteins is controlled by pro and anti apoptotic members of Bcl family of proteins. • Bcl-2,Bcl-x and Mcl-1 are anti apoptotic proteins they inhibit apoptosis.
- 16. • When cellsare deprived of survival singals or their DNA is damaged or misfolded proteins induces ER stress,sensors of damage or stress are activated. • These sensors are also members of Bcl family.they include proteins called Bim,Bid,and Bad. • The sensors activate two critical effectors Bax,Bak
- 17. EXTRINSIC PATHWAY • Deathreceptors are members of TNF receptor family . • Best known death receptors are type 1 TNF receptor and related protein called Fas (CD95). • The machenism of apoptosis induced by these death receptor expressed on many cell types. • Fas is expressed on T cells that recognize self antigens and on some cytotoxic T lymphocytes.
- 18. • When FasLbinds to Fas,three or more molecules of Fas are brought togather and there cytoplasmic death domains form a binding site for a adapter protein that also contains a death domain and is called FADD. • FADD than activated the inactive form of pro caspase-8 to active form of caspase-8. • This pathway of apoptosis can be inhibited by a protein called FLIP.
- 19. • After intiatingpathways the executioner phase is activated,executioner caspases iclude caspase 3 and 6. • These caspases once activated,cleave an inhibitor of cytoplasmic DNase,thus DNase enzyme activated,this Dnase enzyme break down of DNA into nucleosome. • Caspaes degraded structural component of nuclear matrix & thus promote fragmentation of nuclei.
- 20. REMOVAL OF DEADCELLS • In healthy cells phosphatidylserine is present on inner leaflet of plasma membrane but in apoptotic cells this phospholipid flips out and is expressed on outer layer where it is recognized by several macrophage receptors.which help in removal of death cells.
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Editor's Notes
- #6 During development many cells are produced in excess which eventually undergo programmed cell death
- #8 A particularly instructive example for the implication of programmed cell death in animal development is the formation of free and independent digits by massive cell death in the interdigital mesenchymal tissue [Zuzarte-Luis, 2002]. Other examples are the development of the brain, during which half of the neurons that are initially created will die in later stages when the adult brain is formed [Hutchins, 1998] and the development of the reproductive organs [Meier, 2000]. Also cells of an adult organism constantly undergo physiological cell death which must be balanced with proliferation in order to maintain homeostasis in terms of constant cell numbers. The majority of the developing lymphocytes die either during genetic rearrangement events in the formation of the antigen receptor, during negative selection or in the periphery, thereby tightly controlling the pool of highly efficient and functional but not self-reactive immune cells and at the same time keeping lymphocyte numbers relatively constant [Rathmell, 2002]. Taken together, apoptotic processes are of widespread biological significance, being involved in e.g. development, differentiation, proliferation/homoeostasis, regulation and function of the immune system and in the removal of defect and therefore harmful cells. Thus, dysfunction or dysregulation of the apoptotic program is implicated in a variety of pathological conditions. Defects in apoptosis can result in cancer, autoimmune diseases and spreading of viral infections, while neurodegenerative disorders, AIDS and ischaemic diseases are caused or enhanced by excessive apoptosis [Fadeel, 1999a].
- #13 Role of mitochondria in apoptosis Mitochondria play an important role in the regulation of cell death. They contain many pro-apoptotic proteins such as Apoptosis Inducing Factor (AIF), Smac/DIABLO and cytochrome C. These factors are released from the mitochondria following the formation of a pore in the mitochondrial membrane called the Permeability Transition pore, or PT pore. These pores are thought to form through the action of the pro-apoptotic members of the bcl-2 family of proteins, which in turn are activated by apoptotic signals such as cell stress, free radical damage or growth factor deprivation. Mitochondria also play an important role in amplifying the apoptotic signalling from the death receptors, with receptor recruited caspase 8 activating the pro-apoptotic bcl-2 protein, Bid. Role of Bcl-2 proteins The bcl-2 proteins are a family of proteins involved in the response to apoptosis. Some of these proteins (such as bcl-2 and bcl-XL) are anti-apoptotic, while others (such as Bad, Bax or Bid) are pro-apoptotic. The sensitivity of cells to apoptotic stimuli can depend on the balance of pro- and anti-apoptotic bcl-2 proteins. When there is an excess of pro-apoptotic proteins the cells are more sensitive to apoptosis, when there is an excess of anti-apoptotic proteins the cells will tend to be more resistant. An excess of pro-apoptotic bcl-2 proteins at the surface of the mitochondria is thought to be important in the formation of the PT pore. An animation illustrating the general principles is shown below. The pro-apoptotic bcl-2 proteins are often found in the cytosol where they act as sensors of cellular damage or stress. Following cellular stress they relocate to the surface of the mitochondria where the anti-apoptotic proteins are located. This interaction between pro- and anti-apoptotic proteins disrupts the normal function of the anti-apoptotic bcl-2 proteins and can lead to the formation of pores in the mitochondria and the release of cytochrome C and other pro-apoptotic molecules from the intermembrane space. This in turn leads to the formation of the apoptosome and the activation of the caspase cascade. The release of cytochrome C from the mitochondria is a particularly important event in the induction of apoptosis. Once cytochrome C has been released into the cytosol it is able to interact with a protein called Apaf-1. This leads to the recruitment of pro-caspase 9 into a multi-protein complex with cytochrome C and Apaf-1 called the apoptosome. Formation of the apoptosome leads to activation of caspase 9 and the induction of apoptosis. The role of mitochondria in the induction of apoptosis is summarised in the figure below.
- #22 Apoptosis can be triggered by various stimuli from outside or inside the cell, e.g. by ligation of cell surface receptors, by DNA damage as a cause of defects in DNA repair mechanisms, treatment with cytotoxic drugs or irradiation, by a lack of survival signals, contradictory cell cycle signalling or by developmental death signals. Death signals of such diverse origin nevertheless appear to eventually activate a common cell death machinery leading to the characteristic features of apoptotic cell death.