14-Programmed Cell Death (PCD) in eukaryotes

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Importance of PCD in animals and plants?
Regulation of cell numbers Developmental importance Body function, e.g. sculpting structures Elimination of diseased or dangerous cells (e.g. cancer)
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Hallmarks of necrosis?
external trigger (unspecific)/no genetic program->NOT a type of PCD!/ no signal transduction/cytoplasmic swelling/moderate chromatin condensation/expansion of organelles (mitochondria, ER, Golgi)/rupture of the plasma membrane/inflammation response
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Hallmarks of apoptosis?
external or internal signal/signal transduction/defined catabolism of components/chromatin condensation/nucelus frag/almost no morph mods of organelles/cell shrinkage/intact mito&PM/PM blebbing/cellular disent./deg. in phagocyt lysosomes of adj cells
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Describe the intrinsic apoptosis pathway
UV, radiation, chemo, hypoxia->mitochondrion cytochrome C release->apoptosome formation->effector caspases activated -> apoptosis
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Describe the extrinsic apoptosis pathway
adaptor protein and procaspase recruitment to PM ->inhibitor caspase-8 activatin ->mitochondril membrane permeabilisation and effector caspases activated -> apoptosis
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Main differences between the intrinsic and extrinsic pathways?
Intrinsic pathway: have signalling pathway formed (the apoptosome) Extrinsic pathway: external signalling activates cell death (DISC – death inducing signalling complex)
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How is the DISC (death inducing signalling complex) which activates death signalling downstream formed?
killer lymphocyte has Fas (cell death) ligands->bind to Fas death receptors->interact w FADDs which interact w death receptor and death effector domain interacts w that of caspases-> DISC formed
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What are death receptors and death ligands involvedin the extrinsic pathway?
Death receptors: Tumor Necrosis Factor Receptor (TNFR) superfamily „Death“ ligands: Bind specifically to one or multiple receptors
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What is DISC?
DISC is signalling platform of the extrinsic pathway and forms upon ligand binding to death receptor Prerequisite to activate apoptotic signalling->caspaseactivation->initiator& effector caspases
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What are caspases?
Caspases (cysteinyl-aspartate specific protease): Proteolytic enzymes that cleave their substrates at defined positions (different ones in intrinsic and extrinsic pathways)
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What are executioner caspases?
effector caspases:executioner caspases like caspase 7 have 2 types of cleavage (cleavage of N terminal peptide and activation cleavage which splits the small and the large subunits of the caspase so they can be active)->cysteine residue
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describe activation cleavage of executioner caspases
caspase 7 = dimerised-> undergoes activation cleavage which changes the conformation of the caspase 7-> now substrates can bind and enter active site of caspase 7 – they have 2 active active sites on the respective monomers of the caspase
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WHat are intiiator caspases?
Initiator caspases and generally activated by dimerization NOT cleavage e.g. caspase 9 – they also only have one active site
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How is apoptosis regulated in the intrinsic pathway?
Apoptosome assembly and activation by cytochrome c
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What is the apoptosome?
a wheel like structure – an oligomere formed from identical monomers(CARD domain (caspase recruiting domain), NB-ARC (nucleotide oligomerisation domain which binds ATP and hydrolyses it ), WD40 repeats (important for later cytochrome C binding)
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How is apoptosome formed?
Monomer binds ATP->compact structure semi-opens->ATP needs to be hydrolysedas cytC binds to WD40->semi-opening of monomer doesn't allow oligomer forming->ATP which was used &now sits as ADP needs to be replaced with a fresh ATP->propellar structure
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Role of the apoptosome?
signalling platform that activates the intrinsic pathway (Propeller structure when formed can further interact with caspases which are then active and can activate downstream caspases Cytochrome C release from mitochondria activates this)
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How is apoptosis regulated in the intrinsic pathway?
Cytochrome C is formed at mitochondria and released at one point of PCD pathway. Cytochrome C sits at the mitochondrial membrane and is part of the oxidative phosphorylation
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Where is cyctochrome C released from and why?
the inner mitochondrial membrane to activate apoptotic signalling in the cytosol
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What happens If there is a stress that activates the cell death pathway that involves the intrinsic pathway?
mitochondria is permeabilised by BAK&BAX proteins that form channels in OM of mitochondria->disturbance of mitochondria (loses its transmembrane potential)->cytC is released from membrane when cardiolipins are released->leaves mito->ends at APF1
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Mitochondrial membrane permeabilisation (MMP) involves what?
1. Mitochondrial outer membrane permeabilisation (MOMP) by BAX/BAK at the outer membrane (OM) 2. Mitochondrial permeability transition (MPT) by Ca2+ and ROS at the inner membrane (IM) opens the Permeability Transition Pore Complex (PTPC)
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Role of anti-apoptotic proteins?
Can inhibit cell death: Bcl-2 family: Act in the intrinsic pathway (NOTE: Pro-apoptotic BAX and BAK are also Bcl-2 family members) Inhibitor of Apoptosis (IAP) family: Act in the intrinsic and extrinsic pathway
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Role of IAP family proteins?
act as E3 ligases->Ubiquitination of specific pro-apoptotic proteins (e.g. caspases)->RING domain is essential E3 ligase activity
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Which Some biochemical and morpho-logical hallmarks of PCD are not conserved in eukaryotes?
No “true” death receptors in plants.Vacuole in PCD.Cytochrome c is released (function in PCD?).No Bcl-2 family.No caspases,
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Importance of PCD?
plays critical roles in various developmental processes and defense responses e.g.Formation of trachery elements Lignification (xylogenesis) Organ development Senescenceabiotic and biotic stress
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What do biotrophic pathogens do?
Colonise living plant cells
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What do necrotrophic pathogens do?
Kill plant cells before colonisation
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What is a hypersensitive reaction?
immune reaction that stops biotrophic pathogens
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What is necrosis?
pathogenicity mechanism of necrotrophs to colonise plants
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Plants transformed with mammalian inhibitors of apoptosis do what?
stop leaf infection by necrotrophic pathogens
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Role of caspases in plant PCD?
Plants don't have caspases, but distantlyrelated Metacaspases (MCs) &Vacuolar Processing Enzymes(VPEs) have been identified & have caspase activities & participate in plant PCD- Indicates convergent evolution of similar PCD pathways in plants&mammals
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Card 2

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Hallmarks of necrosis?

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external trigger (unspecific)/no genetic program->NOT a type of PCD!/ no signal transduction/cytoplasmic swelling/moderate chromatin condensation/expansion of organelles (mitochondria, ER, Golgi)/rupture of the plasma membrane/inflammation response

Card 3

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Hallmarks of apoptosis?

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Preview of the front of card 3

Card 4

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Describe the intrinsic apoptosis pathway

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Card 5

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Describe the extrinsic apoptosis pathway

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