Apoptosis Cell death o Normal in physiology (death can be physiological) o In disease o In healthy adults millions of cells die in the bone marrow and intestines every hour o Our tissues do not shrink because of a complex regulatory mechanism and balancing with cell division · Removes damaged, unwanted or diseased cells · Programmed cell death = ordered cell deletion · Model systems have underpinned current knowledge · Highly conserved from worm to man C.elegans o Powerful model system o 191 predictable deaths in development o Highly tractable system- easy to control and modify to understand the mechanism o Study regulation, activation and execution of apoptosis · Provided most current information on apoptosis · Apoptosis is crucial for o Development o Maintenance o Control Cell population control · Proliferation = cell division · Differentiation- cells turning into different cells Differentiation -/+ Proliferation + Cell Population Cell Death The importance of apoptosis overactive apoptosis · o neurodegeneration o immunodeficiency o stroke o coronary heart disease o transplant rejection underactive apoptosis o cancer o autoimmune and inflammatory conditions (SLE + RHEUMATOID) life - death imbalance can be desirable (physiological) · underactive apoptosis o allows cell accumulation (e.g. accumulation of cells during an immune response) · overactive apoptosis o returns cell populations to normal after challenge o neutrophil apoptosis during inflammation o CTL death (cytotoxic T lymphocyte death) Characteristics of apoptosis Apoptosis · Cell shrinkage · Organelle integrity · Chromatin condensation · Plasma membrane integrity · Thermodynamics uphill · Internal control · Purposeful Necrosis · Cell swelling · Organelle disruption · Nuclear swelling · Plasma membrane rupture · Thermodynamics downhill · External 'control' · Accidental Key Control Point Death as a default High incidence (10€/sec) Phases of apoptosis I
· Signal is either -ve or +ve / absent or present which can cause an activation or disruption in the cell . If activated the apoptotic pathway can be initiated (apoptotic engine) · Executed apoptosis · Phagocytes can completely degrade the cell Phases of apoptosis II (more detail) · Signals o -ve signals " Cytokine deprivation · Genotoxic damage (chemical/radiation damaging DNA) · Death receptor ligation · Activation Cytokine deprivation leads to survival signals Signals + Activation · Execution Cytokine Deprivation Survival Signals Genotoxic Damage p53 Apoptosis Engine Death Receptor Ligation Caspase 8 Extracellular Intracellular Phagocytosis Degradation o Genotoxic damage leads to p53 o Death receptor ligation leads to caspase 8 · These activate the apoptosis engine which will cause the cell to be destroyed . (the apoptosis engine is also called the caspase cascade which is very highly controlled) Caspases . Proteases o In particular Cysteinyl ASPartate- specific proteases · Key cysteine in active site QACxG · Aspartate at P1 of substrate tetrapeptide · Tetrapeptide defines caspase specificity P4 P1 X-X-X-X-x-x-x(D/I/V/LE-x-D-x-x-x-x-x-x- -x P3 P2 . The caspase will cute at P1 Caspase cascade one molecule of active caspase X LLL cleavage of cytosolic protein many molecules of active caspase Y LLLLL LLLL cleavage of nuclear lamin even more molecules of active