APOPTOSIS ppt

Information about APOPTOSIS ppt

Published on July 14, 2014

Author: NischalTyagi

Source: authorstream.com

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APOPTOSIS: APOPTOSIS Efforts By : NischalTyagi B.pharm , 3 rd year Mentor : Dr.Neerupma Amity University The significance of apoptosis: The significance of apoptosis During development many cells are produced in excess which eventually undergo programmed cell death and thereby contribute to sculpturing many organs and tissues 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 Significance of apoptosis: Significance of apoptosis Due to its importance in such various biological processes, a poptosis is a widespread phenomenon, occuring in all kinds of metazoans such as in mammals, insects , nematodes, and cnidaria . Apoptosis is also an integral part of the life cycle of other unicellular eukaryotes and that even prokaryotes sometimes undergo regulated cell death. Morphological features of apoptosis: Morphological features of apoptosis Apoptotic cells can be recognized by stereotypical morphological changes: the cell shrinks, shows deformation and looses contact to its neighbouring cells. Its chromatin condenses and marginates at the nuclear membrane, the plasma membrane is blebbing or budding, and finally the cell is fragmented into compact membrane-enclosed structures, called 'apoptotic bodies' which contain cytosol , the condensed chromatin, and organelles Apoptotic versus necrotic morphology: Apoptotic versus necrotic morphology Apoptotic versus necrotic morphology Molecular mechanisms of apoptosis signalling pathways : Molecular mechanisms of apoptosis signalling pathways Various death signals activate common signalling pathways Caspases are central initiators and executioners of apoptosis Extrinsic apoptosis pathways of type I and type II Mitochondria as central regulators of intrinsic apoptosis pathways Various death signals activate common signalling pathways: Various death signals activate common signalling pathways 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. Much of the understanding of cell death has come from genetic studies in the nematode C. elegans The proximal cause of apoptosis in C. elegans is the activation of the cysteine protease ced-3. Activity of the ced-3/ced-4 complex is regulated by the apoptosis inhibitor ced-9 and the apoptosis inducer Caspases are central initiators and executioners of apoptosis : Caspases are central initiators and executioners of apoptosis The term caspases is derived from cysteine -dependent aspartate -specific proteases.In the cell, caspases are synthesized as inactive zymogens, the so called procaspases . In extrinsic apoptosis pathways , e.g. procaspase-8 is recruited by its DEDs to the death inducing signalling complex (DISC), a membrane receptor complex formed following to the ligation of a member of the tumor necrosis factor receptor (TNFR) family. When bound to the DISC, several procaspase-8 molecules are in close proximity to each other and therefore are assumed to activate each other by autoproteolysis . Receptor-mediated caspase activation at the DISC: Receptor-mediated caspase activation at the DISC Extrinsic apoptosis pathways of type I : Extrinsic apoptosis pathways of type I Extrinsic apoptosis signalling is mediated by the activation of so called “death receptors” which are cell surface receptors that transmit apoptotic signals after ligation with specific ligands . Death receptors belong to the tumor necrosis factor receptor (TNFR) gene superfamily , including TNFR-1, Fas /CD95, and the TRAIL receptors DR-4 and DR-5 . All members of the TNFR family consist of cysteine rich extracellular subdomains which allow them to recognize their ligands with specificity, resulting in the activation of the respective death receptor . Subsequent signalling is mediated by the cytoplasmic part of the death receptor. The local concentration of several procaspase-8 molecules at the DISC leads to their autocatalytic activation and release of active caspase-8,which then cleave specific substrates resulting in cell death Extrinsic apoptosis pathways of type II: Extrinsic apoptosis pathways of type II In this case, the signal coming from the activated receptor needs to be amplified via mitochondria-dependent apoptotic pathways. The link between the caspase signalling cascade and the mitochondria is provided by the Bcl-2 family member Bid. Proapoptotic Bcl-2 family members Bax and Bak induce the release of cytochrome c and other mitochondrial proapoptotic factors into the cytosol Activated caspase-9 subsequently initiates a caspase cascade and ultimately resulting in cell death Mitochondria as central regulators of intrinsic apoptosis pathways: Mitochondria as central regulators of intrinsic apoptosis pathways Besides amplifying and mediating extrinsic apoptotic pathways, mitochondria also play a central role in the integration and propagation of death signals originating from inside the cell such as DNA damage, starvation, as well as those induced by chemotherapeutic drug. Most apoptosis-inducing conditions involve the disruption of the mitochondrial inner transmembrane potential as well as the so called permeability transition (PT), a sudden increase of the inner mitochondrial membrane permeability to solutes . Osmotic mitochondrial swelling with eventual rupture of the outer mitochondrial membrane, resulting in the release of proapoptotic proteins from the mitochondrial intermembrane space into the cytoplasm. Released proteins include cytochrome c, which activates the apoptosome and therefore the caspase cascade and ultimately cell death. Regulatory mechanisms in apoptosis signalling: Regulatory mechanisms in apoptosis signalling Commonly, the activation of apoptosis is regarded to occur when a cell encounters a specific death-inducing signal such as the ligation of a death receptor by ligand or if cells are treated with a cytotoxic drug. This suggests that the apoptosis signalling pathways in viable cells are kept in an inactive state and are only turned on in response to a death stimulus. Therefore, all cells of a multicellular animal might be intrinsically programmed to self-destruct and indeed would die instantaneously unless cell death is continously repressed by survival signals such as provided by other cells of the organism, e.g. growth factors, hormones, nutrients The Bcl-2 family : The Bcl-2 family Bcl-2, an oncogene was the first example of an oncogene that inhibits cell death rather than promoting its proliferation. Mechanism of regulation :- specific apoptotic signals trigger the activation of particular BH3-(only proteins which then interact with antiapoptotic members on the outer mitochondrial but also nuclear/ER) membrane, resulting in the release of Bax -like proapoptotic factors. Bax -like factors then undergo a conformational change and provoke PT(Permeability Transition) and the release of apoptogenic factors. Regulation of apoptosis by the Bcl-2 family: Regulation of apoptosis by the Bcl-2 family Regulation of apoptosis by IAPs : Regulation of apoptosis by IAPs IAPs are a family of antiapoptotic proteins. All IAPs contain(BIR) domains, 70 amino acid motifs, which are essential for the antiapoptotic properties of IAPs because it is the interaction between the BIR domains and caspases that is believed to confer most of the antiapoptotic activity of IAPs. Indeed, XIAP, c-IAP1 and c-IAP2 are thought to directly inhibit caspases-3, -7, and –9 Diseases due to insufficient apoptosis: Diseases due to insufficient apoptosis Disregulation of apoptotic signalling can play a primary or secondary role in various diseases with insufficient apoptosis leading to e.g. cancer (cell acumulation , defective tumor surveillance by the immune system) autoimmunity (failure to eliminate autoreactive lymphocytes) persistent infections (failure to eradicate infected cells) Diseases due to excessive apoptosis: Diseases due to excessive apoptosis whereas excessive apoptosis contributes to e.g. neurodegeneration ( Alzheimers ’ disease, Parkinson’s disease, Huntington’s disease), autoimmunity (uncontrolled apoptosis induction in specific organs), AIDS (depletion of T lymphocytes), and Ischaemia (stroke, myocardial infarction) PowerPoint Presentation: Thanks for lending me your

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