APOPTOSIS Programmed Cell Death A genetically controlled cell suicide pathway The History of the Cell Death Study • First observed in 1842 by a German scientist Carl Vogt in Jent und Gassman, Solothurn 1842; 130 He wrote “The role of the core of the notochord in the formation of the vertebrae is quite simply that its cells are resolved , beginning when the proliferation of the surrounding cartilage exerts pressure on the notochore”. “The light vesicular nuclei of the embryonic cells have disappeared; at least I could not detect any trace of them”. • 1951, Glucksmann, A (in Cambridge Philosophical Society of bilogical review 26, 59) reviewed and rediscovered developmental cell deaths in embryological tissues • 1964, Lockshin, RA and Williams, CM first used the term of “programmed cell death” to describe the breakdown of the intersegmental muscles of silkworms • 1972, three British scientists Kerr, Wyllie and Currie proposed the term of “apoptosis” for morphology of naturally occurring or physiological cell deaths. They recognized the importance of apoptosis and suggested that it is a basic biological phenomenon with wide-ranging implications in tissue kinetics. The Morphology of Apoptosis Cytoplasm shrinks Chromosomes condense and fragment Nuclear membrane breaks down Apoptotic body formation Engulfment of the cell corpse Classification of cell death Cell death Necrotic Physiological apoptosis autophagic other Caspase-dependent Caspase-independent receptor-caspase 8 mitochondria-caspase 9 APOPTOSIS What is it? Why is it important? How is it controlled? What is its role in age-related disease? APOPTOSIS Programmed cell death Orderly cellular self destruction Process: as crucial for survival of multi-cellular organisms as cell division Forms of cell death Necrosis Apoptosis Mitotic catastrophe Passive Active Passive Pathological Physiological or Pathological pathological Swelling, lysis Condensation, Swelling, lysis cross-linking Dissipates Phagocytosed Dissipates Inflammation No inflammation Inflammation Externally induced Internally or Internally induced externally induced Difference Between Apoptosis and Necrosis • Necrosis (pathological cell death): dying cells swell and lyse; toxic contents leak out and result in inflammatory response. • Apoptosis (physiological or programmed cell death): dying cells shrink, are engulfed by other cells, leave no trace, and don’t result in harmful outcomes APOPTOSIS Evolutionarily conserved •Occurs in all animals studies (plants too!) •Stages and genes conserved from nematodes and flies to humans STAGES OF APOPTOSIS Healthy cell DEATH SIGNAL Commitment to die (reversible) EXECUTION (irreversible) Dead cell (condensed, crosslinked) ENGULFMENT DEGRADATION STAGES OF APOPTOSIS Genetically controlled: Caenorhabditis elegans Soil nematode (worm) ces2 ces1 ced9 ced3,4 Healthy cell Committed cell Dead cell BCL2 Caspases C. Elegans genes == mammalian genes Cells are balanced between life and death DAMAGE Physiological death signals DEATH SIGNAL PROAPOPTOTIC ANTIAPOPTOTIC PROTEINS PROTEINS APOPTOSIS: important in embryogenesis Morphogenesis (eliminates excess cells): Selection (eliminates non-functional cells): APOPTOSIS: important in embryogenesis Immunity (eliminates dangerous cells): Self antigen recognizing cell Organ size (eliminates excess cells): APOPTOSIS: important in adults Tissue remodeling (eliminates cells no longer needed): Apoptosis Virgin mammary gland Late pregnancy, lactation Involution (non-pregnant, non-lactating) - Testosterone Apoptosis Prostate gland APOPTOSIS: important in adults Tissue remodeling (eliminates cells no longer needed): Apoptosis Resting lymphocytes + antigen (e.g. infection) - antigen (e.g. recovery) Steroid immunosuppressants: kill lymphocytes by apoptosis Lymphocytes poised to die by apoptosis APOPTOSIS: important in adults Maintains organ size and function: Apoptosis + cell division Cells lost by apoptosis are replaced by cell division (remember limited replicative potential of cells) APOPTOSIS: control Receptor pathway (extrinsic, physiological): FAS ligand TNF Death receptors: (FAS, TNF-R, etc) Death domains Adaptor proteins Pro-caspase 8 (inactive) Caspase 8 (active) Pro-execution caspase (inactive) Execution caspase (active) MITOCHONDRIA Death APOPTOSIS: control Intrinsic pathway (damage): Mitochondria BAX Cytochrome c release BCL-2 BAK BCL-XL BOK BCL-W BCL-Xs Pro-caspase 9 cleavage MCL1 BAD BFL1 BID DIVA B IK NR-13 BIM Pro-execution caspase (3) cleavage Several NIP3 viral BNIP3 proteins Caspase (3) cleavage of cellular proteins, Nuclease activation, Etc. Death APOPTOSIS: control Physiological Intrinsic receptor pathway damage pathway MITOCHONDRIAL SIGNALS Caspase cleavage cascade Orderly cleavage of proteins and DNA CROSSLINKING OF CELL CORPSES; ENGULFMENT (no inflammation) APOPTOSIS: Role in Disease TOO MUCH: Tissue atrophy Neurodegeneration Thin skin etc TOO LITTLE: Hyperplasia Cancer Athersclerosis etc APOPTOSIS: Role in Disease Neurodegeneration Neurons are post-mitotic (cannot replace themselves) Neuronal death caused by loss of proper connections, loss of proper growth factors (e.g. NGF), damage (especially oxidative damage) Neuronal dysfunction or damage results in loss of synapses (synaptosis; reversible) apopsosis (irreversible) PARKINSON'S DISEASE ALZHEIMER'S DISEASE HUNTINGTON'S DISEASE etc. APOPTOSIS: Role in Disease Cancer Apoptosis eliminates damaged cells (damage => mutations => cancer Tumor suppressor p53 controls senescence and apoptosis responses to damage Most cancer cells defective in apoptotic response High levels of anti-apoptotic proteins or Low levels of pro-apoptotic proteins ===> CANCER APOPTOSIS: Role in Disease AGING Aging --> both too much and too little apoptosis (evidence for both) Too much (accumulated oxidative damage?) ---> tissue degeneration Too little (defective sensors, signals? ---> dysfunctional cells accumulate hyperplasia (precancerous lesions) Functions of apoptosis Sculpt body structures, e.g. hand digit Serve some function but no longer needed e.g. tadpole tail of frog. Needed in one sex but not another e.g. Mullerian duct important for female is eliminated in males by apoptosis. Produced in excess, e.g. extra neurons are removed by apoptosis during neurogenesis. Serve in immune system as a defense mechanism to get rid of harmful or damaged cells.
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