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| 6854706843 | Apoptosis | programmed cell death natural process by which individual cells commit suicide without lysis or leakage of the internal cell content no inflammation | 0 | |
| 6854706844 | Apoptosis is associated with | DNA fragmentation, cytoplasmic shrinkage and membrane blebbing, rapid phagocytosis | 1 | |
| 6854706845 | Necrosis | clusters of cells from hours to days undergo inflammation, DNA cleavage into random fragments | 2 | |
| 6854706846 | Apoptosis occurs | embryogenesis, hormone withdrawal, intestinal crypt epithelia, deletion of autoreactive T cells | 3 | |
| 6854706848 | detecting apoptotic cells | DNA fragmentation and laddering, FACS, tunel assay, annexin V staining | 4 | |
| 6854706849 | DNE fragmentation and laddering | apoptosis will be a ladder because fragmented vs. necrotic will be a smear because random | 5 | |
| 6854706851 | Tunel assay | terminal deoxyribonucleotidyl transferase (catalyzes addition of dUTP that produces a brown nuclear stain) | 6 | |
| 6854706853 | components of the apoptosis | signaling regulation catabolism phagocytosis | 7 | |
| 6854706854 | signaling of apoptosis | injury to cell; withdrawal of GF hormones; activation of death receptors cytotoxic T cells | 8 | |
| 6854706855 | injury to cell | low p53 transcription of genes associated with growth arrest (p21) and arrest high p53 apoptosis | 9 | |
| 6854706857 | PTEN | removes phosphates from ser/thr and tyr residues, like from PI3 --> deactivation of PKB --> promotes apoptosis | 10 | |
| 6854706858 | activation of death receptors | death signals Fas L, TNF a bind death receptors TNFR | 11 | |
| 6854706859 | Fas L | expressed by natural killer cells and cytotoxic T-lymphocytes binds to Fas receptor = ligated homotrimer complex FASS binds to intracellular domain of receptor, recruits pro-caspase 8 to caspase 3 = apoptosis | 12 | |
| 6854706860 | TNFa | expressed by macrophages binds to TNFR making ligated homotrimer complex --> TRADD binds to intracellular domain of ligated receptor, recrit FADD (see FasL) or an adapter protein NFkb for SURVIVAL | 13 | |
| 6854706861 | NFkb | for survival when under stress stress --> I-Kb --> IkBa phosphorylation and Ub-mediated proteolysis --> liberates/activates NF-kB --> translocated to nucleus --> induces expression for stress response (such as I-kBa, its own inhibitor) | 14 | |
| 6854706862 | cytotoxic T-cells | T cell receptor and class I MHC --> perforin and granzyme released from T cell | 15 | |
| 6854706863 | granzyme | enters target cell --> releases granzyme B into cytosol --> effector caspace activation | 16 | |
| 6854706864 | perforin | pore-forming in target cell | 17 | |
| 6854706865 | anti-apoptotic | Bcl-2, Bcl-XL, IAPS | 18 | |
| 6854706866 | Pro-apoptotic | Bax, Bim, Bid, Bad, Noxa, Puma, SMAC DIABLO | 19 | |
| 6854706867 | trans membrane | Bcl-2, Bcl-XL, Bax, Bim | 20 | |
| 6854706868 | non transmembrane spanning | Bid, Bad, Noxa, Puma | 21 | |
| 6854706869 | Bcl-2, Bcl-Xl | decrease permeability, preventing release of cyto c | 22 | |
| 6854706870 | Bax | increases permeability, releasing cytoc into cytosol | 23 | |
| 6854706871 | Bcl-2 superfamily of proteins | affect changes to mitochondrial ion permeability | 24 | |
| 6854706872 | SMAC DIABLO | released into cytosol from mitochondria during injury or in response to pro apoptic to inhibit IAPS | 25 | |
| 6854706873 | IAPS | inhibit both initiator and effector caspaces in cytosol, prevent slight and accidental release of cyto c from inappropraite activation | 26 | |
| 6854706874 | mechanism of caspase actiation | cytoc plus Apaf1 activate apoptosome procaspace 9 to caspase 9 to caspase 3 | 27 | |
| 6854706875 | initiator caspases | caspase 9 and 8 | 28 | |
| 6854706876 | caspase 3 | --| PARP --> DNA fragmentation --| ICAD --> DNAse fragments chromatin | 29 | |
| 6854706877 | caspase 3 or 6 | --| nuclear lamins --> nuclear membrane breakdown | 30 | |
| 6854706878 | caspase 8 | activates effector caspases + Bid --> cyto C | 31 | |
| 6854706879 | phagocytosis of apoptotic bodies | by macrophages to prevent spillage of cellular content into surrounding tissues by recognition of cell-cell receptors | 32 | |
| 6854706880 | apoptotic bodies | nuclear fragmentation after membrane blebbing | 33 | |
| 6854706885 | Caspase | A protease with cysteine in the active site. Targets proteins at an aspartic acid. Targets lamins, cytoskeleton, inhibitors of DNase. | 34 | |
| 6854706886 | Procaspase | The zymogen of caspase. Activated by other caspases leading to a caspase cascade. | 35 | |
| 6854706887 | Death Domain | 6 alpha helices and usually found in receptors. | 36 | |
| 6854706888 | Death Effector Domain | on procaspases and binds to the death domain | 37 | |
| 6854706889 | DISC Death Inducing Signaling Complex | An assembled complex which initiates apoptosis. Usually contains Fas-associated protein with a Death Domain FADD which is an adaptor. | 38 | |
| 6854706890 | Fas Protein | When bound by FasL causes Fas Rs to cluster and recruits adaptor proteins on cytoplasmic side. | 39 | |
| 6854706892 | Extrinsic Pathway | Uses Fas protein and a caspase cascade. | 40 | |
| 6854706893 | Caspase 3 | The executioner caspase. Causes DNA fragmentation by removing inhibition of DNase. | 41 | |
| 6854706894 | CAD | caspase induced DNase | 42 | |
| 6854706895 | Instrinsic Pathway | Occurs under conditions of extreme cellular stress. Involves p53. cyto C, Apaf 1 and Pro caspase-9 | 43 | |
| 6854706896 | Release of cytC from mito | induces clustering of Apaf 1 | 44 | |
| 6854706897 | Apaf 1 apoptotic protease activating factor | Is an adaptor protein. Clusters pro caspase-9. | 45 | |
| 6854706898 | Pro caspase 9 | When cleaved causes caspase cascade to begin. | 46 | |
| 6854706899 | Bcl-2 and Bcl-XL | Anti apoptotic signals on mito membrane surface | 47 | |
| 6854706900 | Bad, Bax, Bid | pro apoptotic signals. | 48 | |
| 6854706901 | Bad | Transcribed by p53 | 49 | |
| 6854706902 | Apoptosome | Is an 7 sided wheel of Apaf 1 and cytochrome C. Recruits and activates caspase-9. | 50 | |
| 6854706903 | p53 | Is a pro apoptotic signal at high levels. | 51 | |
| 6854706904 | mdm2 | Ubiquitinates p53 to lead it to be destroyed. | 52 | |
| 6854706905 | ATM | adds an inhibitory phosphate which allows p53 to accumulate. | 53 | |
| 6854706906 | Necrosis | A form of cell death caused by swelling and rupture of the PM of an infected cell. | 54 | |
| 6854706907 | TRADD tumor necrosis factor receptor type 1 associated Death Domain) | Additional adaptor for TNF-alpha induced necroptosis. | 55 | |
| 6854706913 | Low levels of p53 | cell proceeds through cell cycle | 56 | |
| 6854706914 | moderate levels of p53 | cell cycle arrested | 57 | |
| 6854706915 | High levels of p53 | apoptosis initiated | 58 | |
| 6854706916 | Necrotic cell death versus apoptosis | Necrotic cell death elicits an inflammatory response | 59 | |
| 6854706917 | Normal situations for apoptosis | 1) Normal part of developmental program example finger formation 2) Hormone-withdrawal in adult example endometrial breakdown with menstruation 4) Several types of immune cells 5) Immune system killing of virally infected cells | 60 | |
| 6854706918 | Cellular events related to apoptosis | Cells shrink in size Chromatin condenses into multiple well defined masses near nuclear membrane Cell fragments into many membrane bound bodies Adjacent cells take up released bodies by phagocytosis Cellular debris is rapidly degraded in lysosomes of neighboring cells and macrophages | 61 | |
| 6854706919 | Biochemical events of apoptosis | Activation of cell death proteases caspases Protein cross-linking DNA breakdown Changes in membranes cause phagocytic uptake | 62 | |
| 6854706920 | Caspases | Cysteine proteases that typically cut after aspartic acid Formed as zymogens and activated by cleavage Certain caspases are involved at the start of apoptosis Caspase inhibitors will block apoptosis Cytoskeletal proteins and nuclear scaffold proteins are major targets | 63 | |
| 6854706922 | DNA breakdown | ICAD Inhibitor of Caspase Activated D Nase is destroyed by caspase 3, thus activating CAD CAD cuts both double strands of DNA between nucleosomes | 64 | |
| 6854706924 | General scheme of apoptosis | 1) Initiation of signaling pathways external or internal signal 2) Control phase pro versus antiapototic cell desides to remain viable or head toward cell death 3) Terminal phase- result of several "executioner" caspases caspase 3, 6, and 7 4) Living cells take up cell debris by phagocytosis and destroy it | 65 | |
| 6854706925 | Internal initiation pathways | Loss of needed hormone, nutrient depletion Viral or bacterial invasion Cellular and DNA damage (radiation, toxins, free radical damage, chemicals) | 66 | |
| 6854706926 | Internal apoptotic pathway | Bcl 2 related proteins can regulate the release of cytochrome c from mitochondrial membranes Released cytochrome c can activate Apoptosis-Protease Activator Factor Apaf-1 Multiple copies of Apaf 1 and cytochrome c form Apoptosome complex which will activate caspase 9 by proteolytic cleavage | 67 | |
| 6854706927 | Bcl2 proteins | Bcl-2 family members contain regions of homology, known as Bcl 2 homology (BH) domains. There are four of these domains Originally identified in B Cell lymphomas |  | 68 |
| 6854706928 | Specific Bcl 2 proteins | Anti-apoptotic contain BH1-4 - Bcl-2, Bcl-XL Proapoptotic BH1-3 - Bak and Bax Proapoptotic BH3 only - Bid, Bad, Bim | 69 | |
| 6854706929 | Antiapoptotic Bcl 2 | Contain BH14, inhibit release of cytochrome c Bcl 2 overexpression related to lymphoma Bcl XL binds and inhibits Apaf 1 | 70 | |
| 6854706930 | How apoptotic Bcl2 proteins function | These work by blocking action by BH3 only proteins and by binding to Apaf When activated, BH3 only proteins bind to the multi-domain anti-apoptotic Bcl 2 protiens and are inhibited | 71 | |
| 6854706931 | Propoptotic Bcl 2 (BH1-3) | Mediate release of cytochrome c Bak Bax cytoplasmic prior to activation | 72 | |
| 6854706932 | Propoptotic Bcl 2 (BH3 only) | Promote release of cytochrome c Bad Bid activated by proteolysis to tBid caspase 8 Bim | 73 | |
| 6854706933 | How BH3 only pro-apoptotic proteins work | tBid binds to Bak and Bax which can form channels in the mitochondrial membrane and allow for cytochrome c release | 74 | |
| 6854706935 | Internal activation due to DNA damage | ATM and p53 regulate cellular outcome following DNA damage and other cellular forms of stress Cell cycle arrest can occur at G1/S, Mid S or G2/M phases to allow for DNA repair Severe damage will lead to apoptosis in particular cell types | 75 | |
| 6854706936 | 3 possible outcomes of DNA damage | DNA is repaired and cell divides or DNA is repaired and the cell undergoes senescence Severe damage leads to apoptotic death | 76 | |
| 6854706937 | DNA damage and apoptosis | Apoptosis can be triggered by p53 dependent and p53 independent mechanisms both lead to activation of caspase 9 Effects of p53 are mediated by transcription (PUMA) and direct protein-protein interactions (BAX/BAK and BCL-XL) Note: it inhibits BCL-XL but activates BAX/BAK | 77 | |
| 6854706938 | Procaspase 9 | Activated by both p53 dependent and independent mechanisms Active caspase 9 will activate caspases 3, 6, and 7 and lead to irreversible stages of apoptosis Outcome Destruction of cytoskeleton Cellular DNA degradation Blebbing of cells Protein crosslinking and phosphatidylserine externalization | 78 | |
| 6854706940 | External initiation pathway | Initiated by cytotoxic T cells or cytokine factors such as TNFα, tumor necrosis factor alpha. Utilize cell surface receptors with "death domains" or pore (not techinally considered pores now) forming proteins that allow the direct initiation of the caspase cascade. Two examples: FAS mediated apoptosis and Tumor Necrosis Factor mediated apoptosis Dependent on mitochondrial protein release | 79 | |
| 6854706941 | FAS mediated apoptosis | The Fas receptor (CD95) binds the Fas ligand (FasL) causing receptor activation (trimerization). The internal death domains interact with FADD (Fas associating protein with death domains) which in turn mediates the activation of caspase-8. Fas is found on T cells and is of great importance in limiting the immune response Fas is a member of the TNFR superfamily |  | 80 |
| 6854706953 | Difference apoptosis, necrosis and autophagy | Apoptosis- programmed cell death Necrosis- cell digests itself prematurely Autophagy- lysis mediated cell death | 81 | |
| 6854706954 | Features of apoptosis pathway | Cell shrinkage Membrane blebbing Nuclear fragmentation Mitochondria break down releasing cytochrome c Apoptopic body formation PM becomes permeable to small molecules, apoptopic bodies release chemicals such as ATP, which lead macrophages to engulf them | 82 | |
| 6854706955 | Features of necrosis pathway | Swelling of cell due to increase in water, damages organelles Plasma membrane to rupture, spilling cytoplasmic contents Cell lysis in which enzymatic content of ruptured lysosomes digest cell Leads to inflammation response | 83 | |
| 6854706957 | Features of autophagy pathway | Increase in size of cell due to autophagosome formation These fuse with lysosomes which digest cell Can get localised destruction of organelles | 84 | |
| 6854706958 | Significance of apoptosis | Normal development e.g. in early development apoptosis removes interdigital webs in fingers and toes and in immune system activation, forming T and B cells by eliminating nonreactive or self-reactive cells Role in maintenance of cell populations (10^11 cells die per day to ensure tissue homeostasis) Regulation important in disease state; Too much apoptosis can lead to death of neurone e.g. in alzheimer's Too little leads to cancer | 85 | |
| 6854706960 | What are caspases? | Cysteine-aspartic proteases Initiator caspases play a role in regulating apoptosis by triggering a signalling cascade that results in cell death or can activate effector caspases which carry out cell death themselves | 86 | |
| 6854706961 | Features of caspases | Highly conserved proteases in all species Inactive until needed Activated by irreversible cleavage, this is autocatalytic and triggers activation of surrounding caspases by cofactor binding or inhibitor removal High specificity- different caspases responsible for different proteins | 87 | |
| 6854706962 | Disassembly of cells by caspases | Selectively cleave specific proteins to disassemble cells Inactivation of inhibitors of apoptosis bcl-2 or ICAD which binds to CAD making it inactive, casapase 3 cleaves ICAD Break down lamins by effector caspases/ other proteases and disassemble nuclear membrane e.g. activation of DNA cleaving enzymes, such as CAD | 88 | |
| 6854706963 | Structure of inactive caspases | Synthesised as inactive pro-caspases with 3 domains; Highly variable pro-domain interacts with other molecules to regulate their activation Conserved large (20kDa) and small (10kDa) subunits Aspartate at junction between large and small | 89 | |
| 6854706964 | Activation of caspases | Cleavage of procaspase happens at aspartic acid residues located after prodomain and in between large and small subunits Cleavage and the release of the prodomain forms two active caspases which dimerize to form mature active caspase a heterotetramer consisting of two small and two large subunits | 90 | |
| 6854706965 | Apoptosis activation in C.elegans | CED9 inhibits CED4 by binding to it Presence of developmental cues e.g. EGL-1 which binds to CED-9 leads to inactivation of CED-9 so it can no longer bind to CED-4 CED-4 binds to effector caspases like CED-3, activating them, causing apoptosis | 91 | |
| 6854706966 | Signalling pathways of apoptosis | Extrinsic or intrinsic | 92 | |
| 6854706967 | Initiation of intrinsic pathway | Initiated by cellular events such as DNA damage, GF withdrawal, conflicting signals or loss of contact with extracellular matrix. Controlled by Bcl-2 protein family at the mitochondria Causes changes in the permeability of the mitochondrial membrane that results in the release of pro-apoptotic proteins It is the balance between pro- and anti-apoptotic molecules determines whether a cell with undergo apoptosis or not | 93 | |
| 6854706968 | Events of intrinsic pathway | Intrinsic apoptotic stimuli activate Bh3-only proteins leading to BAK and BAX activation and mitochondrial outer membrane permeabilization. Bcl-Xl on mitochondria surface hanged on by Apaf-1. On signalling from these cellular events, Blk binds to Bcl-Xl causing it to dissociate from Apaf-1. Apaf-1 free to activate caspases e.g. following MOMP, various pro-apoptotic proteins are released such as cytochrome c which binds to APAF-1. Induces its oligomerization and forming a structure that activates caspase 9 an initiator caspase This cleaves and activates caspase 3 and 7, executioner caspases which leads to apoptosis DIABLO also leaks out of mitochondria which inhibits inhibitors of apoptosis proteins IAPs | 94 | |
| 6854706969 | Initiation of extrinsic pathway | Initiated by ligand binding to cell surface death receptors | 95 | |
| 6854706970 | Events of extrinsic pathway | Binding of ligand to cell surface death receptors such as CD95 to FADD Fas associated death domain causes their trimerization This brings together intracellular domain of receptors leading to recruitment of adaptor molecules such as FADD and caspase 8 Leads to dimerisation and activation of caspase 8 which can then directly cleave caspase 3 and 7, executioner caspases which leads to apoptosis | 96 | |
| 6854706971 | Convergence of internal and external signals | Crosstalk between pathways occurs through activation of caspase 8, by extrinsic signalling, which cleaves BID. Truncated BID tBID inhibits BCL-2 and activates BAX and BAK. Leading to permeabilization of mitochondrial outer membrane so that apoptogenic proteins can leak out e.g. cytochrome c and DIABLO | 97 | |
| 6854706973 | Bcl-2 | Antiapoptotic proteins inhibits BAX and BAK, reducing apoptosis . | 98 | |
| 6854706974 | Other apoptosis modulators | Oncogenes such as c-myc- overexpression promotes apoptosis Tumour suppressor p53 induces apoptosis | 99 | |
| 6854706975 | p53 affect on apoptosis | Stabilised p53 induces expression of genes involved in apoptosis- importantly proapoptotic members of the Bcl-2 family e.g. Bas and BH3-only Which increase ratio of pro to antiapoptotic Bcl-2 proteins, favouring release of apoptogenic proteins from the mitochondria and caspase activation Activated mdm2 inhibits IAPs | 100 | |
| 6854706976 | p53 and cancer | Loss of p53 shown to confer significant resistance to apoptosis | 101 | |
| 6854706977 | C-myc | Expression deregulated in one-third of cancers Thought to contribute to 1 in 7 of US cancer deaths Myc activation increases levels of ARF which inhibits mdm2, leading to accumulation of p53 C-myc can also alter the balance between pro- and anti-apoptotic proteins independently of p53- induces Bim which suppresses Bcl-2 family members and increases expression of Bax = amplifies mitochondrial apoptotic pathway Dramatically sensitises cells to the apoptotic action of cd95l and TRAIL Many other ways it can alter pathways of apoptosis including it can alter expression of several players in the death receptor pathway | 102 | |
| 6854706979 | apoptosis | programmed cell death ensures normal embryonic tissue development active cellular process | 103 | |
| 6854706980 | morphology of apoptosis | mild convolution, chromatin condenses, cytoplasm condenses nuclear envelope breaks up, nuclear fragmentation blabbing cell fragmentation phagocytosis of apoptotic bodies by a phagocyte | 104 | |
| 6854706982 | ced 3,4 | pro -apoptotic genes when mutated there will be too many undead cells in C. elgans | 105 | |
| 6854706983 | ced-9 | anti-apoptotic gene -- when mutated, all cells die by apoptosis in wormies | 106 | |
| 6854706985 | initiator caspases | dimerize- active - cleave inactive effector caspases which is activating | 107 | |
| 6854706986 | effector caspases | cleave other protein substrates within the cell to trigger the apoptotic process | 108 | |
| 6854706987 | apoptosome | formation: cytochrome c signals from mitochondria bind Apaf 1 causing them to multimerize into a star shape this formation triggers caspase 9 to dimerize and enter the centre of the star this is a pro apoptotic initiator | 109 | |
| 6854706988 | bcl2 family proteins | have high homology through BH3 regions can oligomerize anti apoptotic bcl2 pro apoptotic - badbid and bak bax | 110 | |
| 6854706992 | extrinsic apoptosis (cell murder) | death signals TNFa or Fas bind death receptors activates caspase 8 dimerize which can activate effector caspases, and also cleaved Bid into t-bid - t bid binds bcl2 Bax freedom cyto c released casp 9 is activated which also activates effectors | 111 |
