9 - Control of Cell Death Flashcards

1
Q

Types of cell death

A
  • Programmed cell death
  • Necrosis
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2
Q

Programmed cell death

A
  • A physiological process where cells are eliminated during development and other normal biological processes
  • E.g. Apoptosis, Autophagy
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3
Q

Apoptosis

A

Type 1 cell death

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4
Q

Autuphagy

A

Type 2 cell death

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5
Q

Necrosis

A

Pathological process after exposure to serious physical or chemical insult

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6
Q

Anoikis

A

Delayed cell death associated with build up of autophagy vesicles

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7
Q

Cornification

A

Epithelial cell specific process to produce outer (dead) layer of the skin

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8
Q
A
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9
Q

Pyroptosis, pyronecrosis

A

Infection induced death
of macrophages

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10
Q

Necroptosis

A

‘regulated’ necrosis

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11
Q

Morphological features of apoptosis

A
  • No loss of membrane integrity
  • Aggregation of chromatin at the nuclear membrane
  • Shrinking of the cytoplasm and condensation of nucleus
  • Fragmentation of cell into apoptotic bodies
  • Leaky mitochondria due to pore formation
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12
Q

Biological features of apoptosis

A
  • Strictly regulated process
  • Energy (ATP) dependent
  • Ladder pattern of DNA fragmentation (non random)
  • Prelytic DNA fragmentation
  • Alteration in membrane asymmetry
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13
Q

Physiological significance of apoptosis

A
  • Evoked by physiological stimuli (growth factors etc)
  • Affects individual cells
  • Phagocytosis by macrophages or adjacent cells
  • No inflammatory response
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14
Q

Morphological features of necrosis

A
  • Loss of membrane integrity
  • Swelling of cytoplasm and mitochondria
  • Total cell lysis
  • No vesicle formation
  • Disintegration (swelling) of organelles
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15
Q

Biological features of necrosis

A
  • Loss of regulation of ion homeostasis
  • No energy requirement
  • Smear pattern of DNA (random digestion)
  • Postlytic DNA fragmentation
  • Possibility for recovery after reversible injury (unlike apoptosis)
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16
Q

Physiological significance of necrosis

A
  • Evoked by non-physiological disturbance
  • Affects groups of cells
  • Phagocytosis by macrophages
  • Significant inflammatory response
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17
Q

What mediates the events associated with apoptosis

A

Caspases

18
Q

Pathways to apoptosis

A
  • Can be extrinsic or intrinsic
  • Apoptosis induction –> Initiator caspase activation –> Effector caspase activation –> Death substrate cleavage –> Apoptosis
19
Q

Regulation of apoptosis

A
  • Positive modulators (pro-apoptosis)
  • Negative modulators (anti-apoptosis)
20
Q

BCL-2 Family

A
  • Inhibitors of apoptosis (anti-apoptosis): Bcl-2, Bcl-xL
  • BH3 only (pro-apoptosis): Bid, Bim Bad
  • Effectors (pro-apoptosis): Bax, Bak, Bok
21
Q

Anti-apoptotic Bcl-2 family structure

A

Four Bcl-2 homology domains (BH) as well as a putative trans
-membrane domain (TM) responsible for their preferred localization at inner membranes.

22
Q

Effector Bcl-2 family structure

A

Bax subfamily resemble Bcl-2
closely in structure possessing three out of four (multiple) BH domains

23
Q

BH3 only Bcl-2 family structure

A

Only share one BH3 domain with all other Bcl-2 family members.

24
Q

Balance between anti-apoptotic and pro-apoptotic Bcl-2 family members

A

Determines if effector members are free to initiate apoptosis

25
Q

Positive modulators of apoptosis (inducers)

A
  • Cytochrome c
  • Apoptosis protease activating factor 1 (APAF1)
  • Caspases
  • Apoptosis inducing factor (AIF)
  • Endonuclease G (Endo G)
  • Granzyme A (GrA)
26
Q

Cytochrome-c

A

Activates APAF1

27
Q

APAF1

A

Critical component of apoptosome, cleaves caspase 9

28
Q

AIF

A

Induces chromatin condensation and DNA degradation

29
Q

EndoG

A

Facilitates chromatin condensation with AIF

30
Q

GrA

A

Serine protease released by cytotoxic T cells

31
Q

E2F

A
  • Transcriptionally activates many pro-apoptotic genes
  • E.g. Bax, Bad, APAF1
32
Q

Negative modulators of apoptosis (inhibitors)

A
  • Bcl-2 family genes
  • Inhibitor of apoptosis proteins (IAPs) that block caspase activation
  • Pro-thymosin-α (ProTα) that blocks apoptosome formation
  • E1B: acts like Bcl2 to bind Bcl2 family effectors
33
Q

NF-kB

A
  • Activation leads to enhanced
    survival
  • Inhibition of NF-kB promotes
    apoptosis
34
Q

Methods for studying apoptosis

A

Utilised in studies of:
- Immunology
- Embryology
- Aging
- AIDS
- Neurology
- Cancer

35
Q

Methods for studying apoptosis

A
  • Protease activity (caspase 3)
  • Membrane alterations
  • DNA fragmentation assay
  • DNA strand breaks
36
Q

Membrane alterations

A
  • Phosphatidylserine translocation to outside of cell when cell undergoes apoptosis
  • Annexin V (a phospholipid-binding protein with a high affinity for phosphatidylserine)
37
Q

DNA fragmentation assay

A
  • Apoptotic DNA ladder
  • Gel electrophoresis
38
Q

DNA strand breaks

A

TUNEL assay (terminal deoxynucleotidyl transferasemediated dUTP nick end labelling)

39
Q

Internal pathways of how cancer cells avoid apoptosis

A
  • p53 loss of function
  • Rb inactivating mutations
  • Myc gene amplification
  • Bcl2 activation
  • Bax inactivating mutations
  • Caspase inactivating mutations
40
Q

External pathways of how cancer cells avoid apoptosis

A
  • Loss of pro-apoptotic signaling molecules
  • Viral infection can prevent apoptosis (e.g. HPV E6 protein blocking p53 function)
  • Interaction with other cells (hide from CTLs)
  • Interaction with chemicals
41
Q

Apoptosis and cancer therapy

A
  • Inducing apoptosis of cancer cells is an ideal therapeutic approach as it prevents inflammation and damage due to necrotic cell death and harnesses the cells own apoptotic machinery
  • But cancerous cells are resistant to apoptosis
  • Need to know affected pathways to produce targeted
    therapies
42
Q
A