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BS3054 > 23rd Nov - Cell Death > Flashcards

23rd Nov - Cell Death Flashcards

1
Q

Describe accidental cell death

A

Cells exposed to extreme stimuli succumb in a completely uncontrollable manner reflecting the immediate loss of structural integrity

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2
Q

Describe regulated cell death

A

Initiated by genetically encoded machinery in response to an extracellular signal

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3
Q

Describe programmed cell death

A

Regulated cell death that occurs as part of the developmental program or to protect tissue homeostasis

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4
Q

What are the four types of cell death?

A

Necrosis
Apoptosis
Autophagy
Conification

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5
Q

What are the universally applicable criteria for assessing cell death?

A

Loss of plasma membrane integrity

Cell fragmentation

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6
Q

How can loss of plasma membrane integrity be detected?

A

IF microscopy

FACs to asses the exclusion of vital dyes e.g. tryphan blue

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7
Q

How can cell fragmentation be detected?

A

IF microscopy

FACs quantification of hypodiploid events

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8
Q

Outline the progression of regulated cell death

A
  1. Homeostatic Pertubation
  2. Signal Transduction
  3. Point of no return
  4. Signal transduction
  5. RCD Correlates

OR

  1. RCD causes
  2. Primary RCD
  3. Release of DAMPs
  4. Inflammatory reactions and initiation of secondary RCD
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9
Q

Give an example of a molecular criteria used in cell death

A

Massive activation of caspases - part of the classic apoptotic programme

Mitochondrial membrane potential dissipation - protracted MM potential dissipation usually proceeds MMP and cell death however transient dissipation is not always a lethal event

Mitochondrial transmembrane permeabilisation (MMP) - complete MMP results in the liberation of lethal catabolic enzymes or activators of such enzymes

Phosphoserine exposure - on the outer leaflet of the pm is often an early event of apoptosis but may be reversible by the upregulation of scramblases

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10
Q

How can massive activation of caspases by identified?

A

Immunoblotting

FACs quantification

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11
Q

How can mitochondrial membrane dissipation be identified?

A

FACs (flow cytometry) quantification with mitochondrial membrane sensitive probes and calcineurin

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12
Q

What is FACs?

A

Fluorescence activated cell sorting, a form of flow cytometry, in which a heteregeneous mixture of cells can be sorted one cell at a time using the specific light scattering and flourescence properties of each cell

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13
Q

How can mitochondrial transmembrane permeabilisaiton (MMP) be identified?

A

IF colacalisation studies

Immunoblotting after subcellular fractionation

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14
Q

How can phosphoserine exposure be identified?

A

FACs quantification of Annexin V binding

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15
Q

What are the morphological features of apoptosis?

A

Rounding up the cell
Retraction of pseudopodes (cytomplasmic projections)
Pyknosis
Karyorrhexis
Minor modification of cytoplasmic organelles
Plasma membrane blebbing
Engulfment by resultant phagocytes

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16
Q

What is pyknosis?

A

Reduction of cellular and nuclear volume

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17
Q

What is karyorrhexis?

A

Nuclear fragmentation

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18
Q

Who won the nobel prize in physiology or medicine in 2002?

A

Brenner, Honitz and Sulston for their work on programmed cell death in Caenorhabiditis elegans

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19
Q

How many initial somatic cells are eliminated by apoptosis?

A

131/1090

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20
Q

Outline the process of apoptosis in C. elegans

A

EGL1 –| Ced-9 –| Ced-4 –> Ced-3

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21
Q

What is the human homolog of CED-3?

A

Caspase

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22
Q

What is the human homolog of CED-4?

A

Apaf-1

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23
Q

In C. Elegans how is the apoptotic pathway regulated?

A

CED-9 binds and negatively regulates CED-4, inhibiting apoptosis. Death is activated by EGL-1 displacing CED-4.

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24
Q

Outline the mammalian apoptosis pathway

A

Bid, Bim –| Bcl-2, Bcl-XL –| Bax, Bak –> Apaf1 –> Caspase 8/9 –> Caspase 3

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25
Q

Which are the caspases that initiate cell death?

A

Caspase 10, 2, 9 and 8

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26
Q

Which are the caspases that execute cell death?

A

Caspase 3, Caspase 6 and Caspase 7

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27
Q

Which are the caspases that cause inflammation?

A

Caspase 1, Caspase 5 and Caspase 4

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28
Q

What is a DED domain?

A

Death effector domain - common in caspases

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29
Q

What is a CARD domain?

A

Caspase activation and recruitment domain -common in capsases

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30
Q

How are caspases activated?

A

They are synthesised in zymogen form thus activated by cleaving

Initator caspases (2,9,8,10) directly cleave Effector caspases (3,6,7)

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31
Q

What is the caspase catalytic triad?

A

Cys-His-Carbonyl

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32
Q

What does the additional interaction of Caspase 2 at residue S5 do?

A

Enhance catalysis at least 30 fold

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33
Q

What are the targets of caspases?

A 
Caspases
Bid
DFF45/ICAD
NDUF51
IAPs
Nuclear Lamins
Catenins
Vimentin
DNA-PK
Rad 51
ATM
p21
Wee1
Rb
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34
Q

What is CAD?

A

Caspase activated DNA fragmentation factor

35
Q

How is CAD activated?

A

Caspase 3 cleaves it

36
Q

What sets the threshold of intrinsic apoptotic pathway susceptibility and how?

A

The anti-apoptotic BCL-2 : pro-apoptotic BCL-2, as they regulate the mitochondrial outer membrane permeabilization

37
Q

What is a BIR?

A

A Baculoviral IAP repeat found in apoptotic proteins, cytokine production proteins and proteins involved in chromosome segregation

38
Q

What is RING?

A

Really interesting new gene, found in many IAPs and encodes a B3 ligase that presumably directs proteins to the ubiquitin-proteasome degradation system

39
Q

What are the proteins that signal phosphatidyl serine exposure?

A 
MFG
E8
GasG
Anxl
Beta1-GP1
ProtS
40
Q

How is the extrinsic apoptotic pathway activated?

A

Through cell surface receptors

41
Q

Outline the three possible signalling pathways of the extrinsic apoptotic pathway

A

A. Death receptor signalling and activation of caspase 8 to caspase 3 cascade

B. Death receptor signalling and activation of caspase 8 to tBID to MOMP to caspase 8 and caspase 3

C. Ligand deprivation induced dependence on receptor signalling followed by activation of the caspase 9 to caspase 3 cascade

42
Q

What are the key events of the intrinsic apoptotic pathway?

A

Generalized and irreversible dissipation of mitochondrial membrane permeability
Release of mitochondrial inner membrane space and proteins into the cytosol
Respiratory chain inhibition

43
Q

What protein is a regulator of crosstalk between classically intrinsic and extrinsic apoptotic signalling pathways?

A

XIAP

44
Q

What are the functions of XIAP?

A

Mediate cross-talk between the intrinsic and extrinsic apoptotic pathways
Rapidly induce caspase 8
Define cell type specific elements of FAS signalling

45
Q

What are the main biochemical features of extrinsic apoptosis by death receptors?

A 
Death receptor signaling
caspase-8 activation
BID cleavage
Increase in mitochondrial outer membrane permeability
Caspase 3 activation
46
Q

What are the possible inhibitory interventions for extrinsic apoptosis triggered by death receptors?

A

CnmA expression
Genetic inhibition of caspases
Z-VAP-fmk administration

47
Q

What are the main biochemical features of the extrinsic apoptotic pathway activated by dependence receptors?

A 
Dependence receptor signalling
PP2A activation
DAPK1 activation
Caspase-9 activation
Caspase-3 activation
48
Q

What are the possible inhibitory interventions of the extrinsic apoptotic pathway activated by dependence receptors?

A

Genetic inhibition of caspases
Genetic inhibition of PP2A
Z-VAD-fmk administration

49
Q

What are the main biochemical features of caspase dependent intrinsic apoptosis?

A

Increase in mitochondrial outer membrane permeability

Irreversible mitochondrial membrane membrane potential dissipation

50
Q

What are the possible inhibitory interventions for caspase dependent intrinsic apoptosis?

A

BCL2 OE

Z-VAD-fmk administration

51
Q

What is Z-VAD-fmk?

A

Cell-Permeant Pan Caspase Inhibitor of Apoptosis

52
Q

What are the biochemical markers of caspase independent intrinsic apoptosis?

A

Release of IMS proteins

Respiratory chain inhibition

53
Q

What are the biochemical markers?

A

Release of IMS proteins

Respiratory chain inhibition

54
Q

What is the possible inhibitory intervention for caspase dependent intrinsic apoptosis?

A

BCL-2 OE

55
Q

What are the morphological features of necrosis?

A

Oncosis
Rupture of plasma membrane
Cytoplasmic organelle swelling
Moderate chromatin condensation

56
Q

What is oncosis?

A

Cytoplasmic swelling

57
Q

What are the biochemical features of necrosis?

A

Activation of calpains

Activation cathespins

58
Q

What activates calpains and cathespins?

A

Massive increase in calcium which is disregulated

59
Q

What is necroptosis?

A

Regulated necrosis

60
Q

What can trigger necroptosis?

A

Alkylating DNA damage, excitotoxins and ligation of death receptors

61
Q

What inhibits necroptosis?

A

necrostatin -1 a chemical RIPK1 inhibitor

62
Q

What is used to identify necroptosis in cells?

A

necrostatin-1

63
Q

What is MLKL?

A

Mixed-lineage kinase domain like protein that causes cell lysis by translocation to the membrane

64
Q

What are the diseases that necroptosis plays a role in?

A 
Artherosclerosis
Ischemiareperfusion injury
Transplantation
Lung infection 
COPD
Remote lung injury
Hepatotoxicity
Alcoholic and non-alcoholic steatiohepatitis
Remote liver injury
Kidney ischemiareperfusion injurt
Bone marrow failure
Crohns and ulcerative colitis
Acute pancreatitits
Traumatic brain injury
Stroke
65
Q

Outline the cycophilin D- mediated mitochondrial permeability transition

A

A caspase independent necrotic pathway which occurs in traumatic brain injury or stroke. Associated with calcium overload, oxidative stress and ATP depletion

Cyp-D binds the active target protein to form a pore traversing the mitochondrial membrane

66
Q

What inhibits CypD-mediated mitochondrial membrane permeability transition?

A

Cyclosporinea

67
Q

What is pyroptosis?

A

A form of regulated necrosis in which Osmotic cell lysis and release of intracellular pro-inflammatory molecules such as ATP and HMGB1

68
Q

What typically initiates pyroptosis?

A

Toll like receptors (TLR) or NOD like receptors (NLR) binding to PAMPs/DAMPs

69
Q

What is parthanatos?

A

A form of regulated necrosis induced through PARP overactivation

70
Q

What is ferroptosis?

A

A form of regulated necrosis dependent on Iron and under the control of glutathione peroxidase 4 (GPX-4)

71
Q

What inhibits ferroptosis?

A

Erastin which inhibits the Glu-Cys exchanger System Xc

72
Q

What are the morphological features of cornification?

A

Elimination of cytosolic organelles
Modifications of the plasma membrane
Accumulation of lipids in F and L granules
Extrusion of lipids in the extracellular space
Desquamation by protease activation

73
Q

What is cornification?

A

A form of active cell death in which the cornified epithelium is formed by the basal lamina dying

74
Q

What are the biochemical features of cornification?

A

Activation of transglutaminases

Caspase-14 activation

75
Q

What is autophagy?

A

consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases

76
Q

Does triggering the autophagic pathway always lead to cell death?

A

No sometimes this process promotes survival by removing dangerous protein aggregates

77
Q

What are the morphological features of autophagy?

A

Lack of chromatin condensation
Massive vacuolization of the cytoplasm
Accumulation of bilameller autophagic vesicles
Litlle or no uptake of phagocytic cells

78
Q

What are the classifications of autophagy?

A

Microautophagy
Chaperone mediated autophagy
Macroautophagy

79
Q

What is microautophagy?

A

Molecules are sequestered at the level of the lysosome

80
Q

What is chaperone mediated autophagy?

A

Entry is chaperone mediated, and molecules are sequestered at the level of the lysosome

81
Q

What is macroautophagy?

A

Has a larger capacity in the pathway therefore can involve much larger protein complexes or organelles

82
Q

Outline the process of macroautophagy

A
  1. A sequesteration crescent is formed, with LC3 and Atg5-12/16 free in the cytoplasm
  2. A phagophore forms with LC3 and atg in its membrane
  3. Autophagosome forms encapsulating the organelle and LC3-II
  4. Intermediate autophagosome forms through fusion with the endosome, containg the organelle, LC3-II and LAMP1/2
  5. The autolysosome forms through fusion with the lysosome encapsulating LAMP1/2, Acid phosphatases and cathespins
83
Q

What are the biochemical features of autophagy?

A

LC3I –> II conversion
Depending on atg gene production
Beclin 1 dissociation from Bcl-2/Xl
p62 LCK degradation

84
Q

What is the clinical relevance of autophagy?

A

Believed to be important for getting rid of protein aggregates such as those causing neurodegenerative diseases

BS3054 (25 decks)

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