Apoptosis ppt


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  • During development many cells are produced in excess which eventually undergo programmed cell death
  • 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 interdigitalmesenchymal 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].
  • Role of mitochondria in apoptosisMitochondria 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 proteinsThe 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.
  • 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.
  • Apoptosis ppt

    1. 1. vkunder637@gmail.com
    2. 2. APOPTOSIS Many observations indicated cell death plays a considerable role during physiological processes Programmed cell death
    3. 3. APOPTOSIS Apoptosis is an energy dependent programmed cell death for removal of unwanted individual cells
    4. 4. • Cells die by one of two mechanisms – • Two physiologically different processes • Apoptosis and necrosis have different characteristics
    5. 5. • Loss of membrane integrity • Begins with swelling of cytoplasm and mitochondria • Ends with total cell lysis, no vesicle formation, complete lysis • Disintegration (swelling) of organelles • Membrane blebbing, but no loss of integrity • Begins with shrinking of cytoplasm and condensation of nucleus • Ends with fragmentation of cell into smaller bodies • Mitochondria become leaky due to pore formation involving proteins of the bcl-2 family.
    6. 6. • Loss of regulation of ion homeostasis • No energy requirement • Random digestion of DNA (smear of DNA after agarose gel electrophoresis) • Postlytic DNA fragmentation (= late event of death) • Tightly regulated process • Energy (ATP)-dependent • Non-random mono- and oligonucleosomal length fragmentation of DNA(ladder type patern) • Prelytic DNA fragmentation • Release of various factors into cytoplasm by mitochondria • Activation of caspase cascade • Alterations in membrane asymmetry
    7. 7. • Affects groups of contiguous cells • Evoked by non-physiological disturbances (complement attack, lytic viruses, hypothermia, hypoxia, ischemia, metabolic poisons) • Phagocytosis by macrophages • Significant inflammatory response • Affects individual cells • Induced by physiological stimuli (lack of growth factors, changes in hormonal environment) • Phagocytosis by adjacent cells or macrophages • No inflammatory response
    8. 8. APOPTOSIS Apoptosis in physiologic situations Apoptosis in pathologic situations
    9. 9. APOPTOSIS Apoptosis in physiologic situations Vaux and Korsmeyer, 1999,Cell
    10. 10. Formation of free and independent digits Development of the brain Development of reproductive organs Apoptosis in physiologic situations Programmed cell death during embryogenesis
    11. 11. Apoptosis in physiologic situations Cell loss in proliferaing cell populations Death of cells that have served their useful purpose Elimination of harmful self- reacttive lymhocytes Programmed cell death during adult stage
    12. 12. Apoptosis in pathologic situations DNA damage Accumulation of mis-folded proteins Cell injury in certain infections Pathological atrophy in parenchymal organs after duct obstruction 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.
    13. 13. Morphology of Apoptosis
    14. 14. Biochemical features of Apoptosis • By activation of caspases • Caspases activate DNAses Protein Cleavage • Cleavage into oligonucleosomes • By Ca2+-and Mg2+-dependent endonucleases DNA Breakdown • Phosphatidylserine • Thrombospondin Phagocytic Recognition
    15. 15. Mechanisms of Apoptosis The fundamental events in apoptosis is the activation of enzymes called CASPASES • Cysteine proteases • Cysteine-dependent ASPartate-specific proteASES Caspases
    16. 16. Mechanisms of Apoptosis Active cysteine residue in the catalytic site Specificity in cleavage after an Asp residue Synthesized as inactive zymogens (PROCASPASES)
    17. 17. • Digestion of DNA starts after 2 hrs • 3&4 hrs after initiation of apoptosis DNA is almost all degraded • DNA is fragmented with restriction endonucleases • Apoptosis induces 180 bp ladderingof DNA
    18. 18. • DNA cleaved into non-random fragments • 180-200 bp fragments & multiples of this unit
    20. 20. • Intrinsic pathway Mitochondrial pathway • Extrinsic pathway The death receptor pathway
    21. 21. • Intrinsic pathway Mitochondria BAX BAK BOK BCL-Xs BAD BID B IK BIM NIP3 BNIP3 BCL-2 BCL-XL BCL-W MCL1 BFL1 DIVA NR-13 Several viral proteins Mitochondrial pathway
    22. 22. The death receptor pathway • Extrinsic pathway
    23. 23. Antiapoptotic Proapoptotic Bcl-2 family members A very large family with 30 members identified and belongs to both: Bid Bim Bik Bad Bmf Hrk Noxa Puma Blk BNIP3 Spike BH1, BH2,BH3,BH4 BH3 BH1, BH2,BH3
    25. 25. APOPTOSIS
    26. 26. REFERENCES Robin’s pathology •7th and 8th Edition Introduction to apoptosis •By Andreas Gewies ApoReview in2003