Cell Death 2 Flashcards

1
Q

One of the targets of caspases includes mediators and regulators of apoptosis. List 5.

A
Caspases
Bid
DFF45/ICAD
NDUFS1
IAPs
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2
Q

One of the targets of caspases includes structural proteins. List 4.

A

Nuclear lamins
Catenins
Vimentin

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3
Q

One of the targets of caspases includes cellular DNA repair proteins. List 3.

A

DNA-PK
Rad51
ATM

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4
Q

One of the targets of caspases includes cell cycle-related proteins. List 3.

A

p21
Wee1
Rb

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5
Q

Which enzyme cleaves DNA during apoptosis?

A

CAD (cleaved from iCAD)

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6
Q

What is MOMP?

A

Mitochondrial Outer Membrane Permeabilisation

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7
Q

What is MOMP mediated/regulated by?

A

BCL-2 family members

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8
Q

Extrinsic apoptosis features one of three signalling cascades. What are these?

A
  1. Death receptor signalling and activation of the caspase-8 to caspase-3 cascade
  2. Death receptor signalling and activation of the caspase-8 to tBID to MOMP to caspase-9 to caspase-3 pathway
  3. Ligand deprivation-induced dependence receptor signalling followed by activation of the caspase-9 to caspase-3 cascade.
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9
Q

What are 4 main targets of caspases?

A
  1. Mediators/ regulators of apoptosis
  2. Structural proteins
  3. Cellular DNA repair proteins
  4. Cell cycle-related proteins
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10
Q

What is intrinsic apoptosis mediated by?

A

MOMP (mitochondrial outer membrane permeabilisation)

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11
Q

What is MOMP?

A

Mitochondrial Outer Membrane Permeabilisation

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12
Q

What three things is intrinsic apoptosis associated with?

A
  1. Generalised and irreversible dissipation of mitochondrial membrane potential
  2. Release of mitochondrial inner membrane space proteins into the cytosol
  3. Respiratory chain inhibition
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13
Q

What is intrinsic apoptosis triggered by?

A
Intracellular stress conditions, including:
DNA damage
Oxidative stress
Ca++ overload
ER stress (unfolded proteins)
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14
Q

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

A

Death receptor signalling
Caspase-8 (-10) activation
BID cleavage and MOMP (in type II)
Caspase-3 (-6,-7) activation

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15
Q

How can extrinsic apoptosis by death receptors be inhibited?

A

CmA expression
Genetic inhibition of caspases (8&3)
Z-VAD-fmk administration

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16
Q

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

A
Dependence receptor signalling
PP2A activation 
DAPK1 activation
Caspase-9 activation 
Caspase-3 (-6,-7) activation
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17
Q

How can extrinsic apoptosis by dependence receptors be inhibited?

A

Genetic inhibition of caspases (9 & 3)
Genetic inhibition of PP2A
Z-VAD-fmk administration

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18
Q

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

A

MOMP

Irreversible mitochondrial transmembrane dissipation

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19
Q

How can caspase-dependent intrinsic apoptosis be inhibited?

A

BCL-2 over expression

Z-VAD-fmk administration

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20
Q

What are the main biochemical features of caspase-independent intrinsic apoptosis?

A

Release of IMS proteins

Respiratory chain inhibition

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21
Q

How can caspase-independent intrinsic apoptosis be inhibited?

A

BCL-2 over expression

22
Q

What TYPE of enzyme are caspases?

A

Proteolytic enzymes that play a key role in apoptotic cell death

23
Q

Give two biochemical features of necrosis

A

Activation of calpains

Activation of cathepsins

24
Q

Give an example of regulated necrosis

A

Necroptosis

25
Q

What can regulated necrosis (eg Necroptosis) be triggered by?

A
  1. Alkylating DNA damage
  2. Excitotoxins
  3. Ligation of death receptors
26
Q

What chemical can inhibit most forms of regulated necrosis?

A

NECROSTATIN-1 (a chemical RIP1 kinase inhibitor)

27
Q

What is necrostatin-1?

A

A chemical inhibitor of RIP1 (therefore inhibits regulated necrosis)

28
Q

What are the 3 main biochemical features of Necroptosis?

A
  1. Death receptor signalling
  2. Caspase inhibition
  3. RIP1 and/or RIP3 activation
29
Q

Give two main biochemical features of cornification

A
  1. Activation of transglutaminases

2. Caspase-14 activation

30
Q

What signals for a cell to be phagocytosed?

A

Flipping of phosphatidylserine from the inner to outer leaflet

31
Q

How does the PI3K/mTOR pathway affect autophagy?

A

Inhibits it via p70(56k)

32
Q

Give 4 biochemical features of autophagy

A

LC3-I to LC3-II conversion
Dependency on atg gene products
Beclin-1 dissociation from Bcl2/Xl
p62(Lck) degradation

33
Q

Which diseases has autophagy been primarily associated with?

A

Neurodegenerative - evidence for the importance of autophagy in the clearance of aggregate-prone proteins, eg those causing neurodegenerative disorders

34
Q

How does inhibition of mTOR affect autophagy?

A

Induces it

35
Q

Inhibition of mTOR induces autophagy. What is the effect of inhibiting mTOR in neurodegenerative diseases like Huntingtons? Why?

A

It induces autophagy which reversed protein aggregation/accumulation

36
Q

Why can mTOR realistically not be inhibited therapeutically?

A

SIDE EFFECTS

37
Q

As mTOR cannot be inhibited, how else may autophagy be induced in cells?

A
  1. L-type Ca++ channel antag
  2. K+ATP channel opener (MINOXIDIL)
  3. Gi signalling activator (CLONIDINE)
38
Q

Name the K+ATP channel opener that can be used to treat diseases like Huntingtons through reversing protein aggregation. How does it do this?

A

MINOXIDIL

Induces autophagy

39
Q

Name the Gi signalling activator that induces autophagy to reverse protein aggregation in diseases like Huntingtons

A

CLONIDINE

40
Q

When might you want to activate cell death?

A

In cancer

41
Q

Which are the functional TRAIL receptors?

A

TRAIL-R1 and TRAIL-R2

42
Q

How do the functional TRAIL receptors TRAIL-R1 and TRAIL-R2 induce apoptosis?

A

Via their DEATH DOMAINS (DDs)

43
Q

What is TRAIL?

A

TNF-related apoptosis-inducing ligand

44
Q

Name some TRAIL-based therapeutics that act as pro-apoptotic agonists at:

1) the TRAIL-R1
2) the TRAIL-R1/R2

A

1) mapatamuab

2) dulanermin

45
Q

Name two drugs that act to downregulate the anti-apoptotic Bcl-Xl, Bcl-2 and Mcl-1 proteins (thus releasing inhibition of Bax and Bak)

A

HAIF-1

ABT-737

46
Q

Name two drugs that inhibit XIAPs such as survivin

A

Cisplatin

SM-164

47
Q

Name a drug that inhibits FLIP, thus releasing inhibition of Caspase 8

A

Quercetin

48
Q

Give an example of a drug that induces apoptosis through inhibiting kinases and down-regulating Bcl-Xl and Bcl-2

A

Flavopiridol

49
Q

Which family of proteins regulate the outer mitochondrial membrane (OMM) permeability, thus controlling the MOMP?

A

Bcl-2 family

50
Q

Anti-apoptotic Bcl-2 over expression may be used to treat which type of diseases?

A

Neurodegenerative