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UNC-Chapel Hill ENVR 442 - Mechanisms of cell death

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Mechanisms of Cell DeathEtiology of cell deathThe road to necrosisPathogenesis of necrosisNecrosis: consequences of irreversible cell injuryTypes of necrosisSlide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Mechanisms ofMechanisms ofCell DeathCell DeathEtiology of cell deathEtiology of cell death Major Factors Accidental Genetic Necrosis Apoptosis Necrosis: Necrosis: The sum of the morphologic changes that follow cell death in a living tissue or organApoptosis: a physiological process that includes specific suicide signals leading to cell deathThe road to necrosisThe road to necrosisHomeostatic ‘steady state’Cellular adaptationsReversible cell injuryIrreversible cell injuryCell death NecrosisPathogenesis of necrosisPathogenesis of necrosisNecrosis: Necrosis: consequences of irreversible cell injuryconsequences of irreversible cell injuryTypes of necrosisTypes of necrosis•Coagulation necrosis (ischemia)•Liquefaction necrosis (escape of hydrolases)•Enzymatic fat necrosis (escape of lipases)•Caseous necrosis (e.g., bacterial liquefaction)•Gangrenous necrosis (ischemic + bacterial liquefaction)Necrosis: a pathological responseto cellular injury Apoptosis: a physiological response to specific suicide signals, or lack of survival signalsChromatin clumpsChromatin condenses and migrates to nuclear membrane. Internucleosomal cleavage leads to laddering of DNA at the nucleosomal repeat length, ca. 200 bp.Mitochondria swell and rupture Cytoplasm shrinks without membrane rupturePlasma membrane lyses Blebbing of plasma and nuclear membranesCell contents spill outCell contents are packaged in membrane bounded bodies, internal organelles still functioning, to be engulfed by neighbours. General inflammatory response is triggeredEpitopes appear on plasma membrane marking cell as a phagocytic target.No spillage, no inflammationwww.chembio.uoguelph.caIn embryonic and fetal development:•Tissue developmental programs which control sculpting of embryonic form•Developmental organization of the nervous system• Elimination of self-reactive components of the immune systemIn the adult:• On stimulation by T-lymphocytes•In response to DNA damage or abnormality, e.g. by radiation, viral infection or transformation•In certain organs and tissues, on withdrawal of supporting hormonesIn addition, there are often apoptotic centers in tumors, accounting for the paradox of slow gross enlargement in the face of rapid cell proliferation, and the rare spontaneous remission.APOPTOSIS AS A PHYSIOLOGICALLYAPOPTOSIS AS A PHYSIOLOGICALLYIMPORTANT PROCESSIMPORTANT PROCESSwww.chembio.uoguelph.caAPOPTOSIS in APOPTOSIS in C.elegansC.elegansC.elegans genome: 19099 genes (790 seven-pass transmembrane receptors, 480 zinc finger proteins, and 410 protein kinases)The life cycle of C. elegans from egg to sexual maturity (and new eggs) is about 3 daysced-1, -3, -4, and -9 (Cell death determining) proteins in C.elegans are closely related to mammalian apoptosis-regulating genesThe adult hermaphrodite consists of exactly 959 somatic cells of precisely determined lineage and function. Individual cells are named and their relationships to their neighbors are knownOverall, the 959 somatic cells of adult C.elegans arise from 1090 original cells; exactly 131 somatic cells undergo programmed cell death in the wild type wormOf the 1090 cells, 302 are neurons, and many of the programmed deaths also lie in the neuronal lineagewww.chembio.uoguelph.caNature Immunology 4, 416 - 423 (2003) Autophagic cell death (type II programmed cell death) – meaning that the cytoplasm is actively destroyed long before nuclear changes become apparent;Classical apoptotic cell death – meaning that the chromatin marginates and the cell and nucleus fragment before morphological changes are seen in intracellular organellesNuclear alterations in different forms of programmed cell death The use of chromatin condensation as a criterion to distinguish apoptosis from apoptosis-like PCD has been inconsistent in the scientific literature, and the potential for overlapping definitions and errors is large. The following examples of classical apoptosis (c,e) and apoptosis-like PCD (b,d,f,g–i) might provide a general guideline. Examples of control chromatin (a), and caspase-independent chromatin margination triggered directly by microinjection of AIF (b). Caspase-dependent strong chromatin compaction (c) versus caspase-independent, AIF-driven lumpy chromatin condensation (d) in PCD of mouse embryonic stem cells. (e) Caspase-dependent chromatin compaction to crescent shaped masses at the nuclear periphery and chromatin fragmentation to two compact spheres (f) or caspase-independent lumpy chromatin condensation without nuclear fragmentation in colchicine-induced neuronal cell death. Incomplete, lumpy chromatin condensation (compare with b,d) in caspase-independent apoptosis-like PCD triggered by Hsp70 depletion (g) or the active form of vitamin D (i), and in caspase-dependent TNF-induced apoptosis-like PCD (i) in caspase-3 deficient MCF-7 cells.Nature Reviews Molecular Cell Biology 2, 589 -598 (2001)Nature Reviews Cancer 2; 647-656 (2002) APOPTOSISAPOPTOSISSIGNALSSIGNALSMitochondria-dependentapoptosisCaspase-dependentapoptosisDeath Receptor-dependentapoptosisCaspase-dependentapoptosisCaspase-independentapoptosisCaspase-independentnecrosisThe target sequence for Ced-3 and caspases (Cys catalytic Asp targeting proteases)consists of a tetrapeptide with C-terminal Asp (D).Methods Enzymol. 2008;442:157-81Methods Enzymol. 2008;442:157-81Earnshaw et al. (1999)Mammalian CaspasesMammalian CaspasesNuclearLamins, nucleoplasmin, the SR protein 70K U1, hnRNP C, RNA Pol I upstream binding factor, the p53 regulator MDM2, pRB, p27 Kip and p21CipDNA relatedMCM3, Repair enzymes including Rad51, poly-ADP-ribose polymerase (PARP), topoisomerase, inhibitor of caspase activated DNase, ( iCAD/DFF45)Cytoskeletonactin, gelsolin, spectrin, keratinCytoplasmicß-catenin, Bcl-2Protein kinasesDNA dependent protein kinase, protein kinase C, CAM kinase, focal adhesion kinase, MAP and ERK kinases, Raf1, Akt1/protein kinase B, ROCK I.In vivo In vivo substrates of effector caspasessubstrates of effector caspaseswww.chembio.uoguelph.caMitochondria play a central


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