Apoptosis Extrinsic Flashcards
1
Q
What are the two general processes by which cells die?
A
Necrosis
Apoptosis
2
Q
Necrosis refers to cell death that results from ______________________.
A
Injury
3
Q
Following necrosis, three things occur. What are they?
A
- Cell swells
- Cell bursts
- Inflammatory response follows
4
Q
Apoptosis refers to cell death that results from ______________, __________________, __________________, and ______________.
A
DNA damage
Withdrawal of essential growth factors or nutrients
Detachment from substrate
Attack by cytotoxic lymphocyte
5
Q
What word means a literal “falling away”?
A
Apoptosis
6
Q
Apoptosis can be caused by external stimuli or internal events; regardles, it is an orderly process where the cell systematically breaks down all of its organells, forming __________ bodies that are picked up by _______________, resulting in no inflammatory response.
A
Apoptotic bodies
Phagocytes
7
Q
What are the three events that comprise apoptosis?
A
- Nucleus fragments
- Cell fragments (apoptotic bodies)
- Fragments are engulfed (by phagocytes), no inflammatory response initiated
8
Q
What does “ischemia” mean?
A
Inadequate blood flow
9
Q
What two things can cause necrosis?
A
Overwhelming toxic insult
Ischemia
10
Q
Necrosis is characterized by cell __________________.
A
Cell swelling
11
Q
Extracellular signals activate the ______________ pathway of apoptosis.
A
Extrinsic
12
Q
What causes apoptosis?
A
Normal development and metamorphosis
13
Q
What are two extracellular signals that can activate the extrinsic apoptotic pathway?
A
Tumor necrosis factors, which are produced by immune cells
Fas ligand, expressed on surface of cytotoxic T cells
14
Q
Internal signals activate the ____________ pathway of apoptosis.
A
Intrinsic
15
Q
What internal signals can activate the intrinsic pathway of apoptosis?
A
DNA damage
Loss of cell-extracellular matrix contact
Insufficient nutrients and/or hormone stimulation
16
Q
What are the four characteristics of apoptosis?
A
- Membrane blebbing
- Organelle, cytoskeleton, and nuclear lamin degradation
- Appearance of phosphatidylserine on the outer leaflet of the plasma membrane
- DNA fragmentation
17
Q
What is known as the “eat me” signal for phagocytes?
A
Phosphatidylserine
18
Q
Appearance of ______________________ on the outer leaf of the plasma membrane function as the “eat me” signals for phagocytes
A
Phosphatidylserine
19
Q
DNA fragmentation leads to a DNA ________________.
A
“laddering”
20
Q
What is a DNA ladder?
A
A banding pattern of DNA where DNA is found in 200 base pair fragments
21
Q
Why does DNA fragment into ladders?
A
Around 200 base pairs wrap around a histone
22
Q
What enzymes are activated during apoptosis?
A
Caspases
23
Q
The enzyme group _____________________ are responsible for the characteristics of apoptosis
A
Caspase
24
Q
What are caspases?
A
Proteases that contain cysteine in their active site and cleave proteins next to aspartate residues in substrates
25
Caspases are ____________ that contain cysteines in their active sites and cleave next to aspartate residues in their substrates
Proteases
26
There are two categories of caspases: ___________ and \_\_\_\_\_\_\_\_\_\_.
Initatior caspases
Executioner caspases
27
What do initiator caspases do?
Initate apoptosis
28
What do executioner caspases do?
Ultimately cause cell death
29
Caspases like all proteins are synthesized in a \_\_\_\_\_-form that must be _______________ cleaved in order to become active.
Pro-form
Protealytically
30
What are the two primary initiator caspases in mammals?
Caspase 8
Caspase 9
31
Initiator caspases are found as inactive _______________ that dimerize upon binding with their ________________ proteins. Once dimerized, they are cleaved, resulting in active initiator caspases.
Monomers
Adaptor proteins
32
When do caspases 8 and 9 become active?
After binding adaptor proteins, dimerizing, and undergoing proteolytic cleavage
33
What activates executioner caspases?
Active initiator caspases (e.g., caspase 8 and caspase 9)
34
What are the three executioner caspases found in mammals?
Caspase 3
Caspase 6
Caspase 7
35
Caspases 3, 6, and 7 are synthesized as _______________ and are activated via dimerization and _______________ cleavage.
Pro-caspases
Proteolytic
36
Executioner caspases cleave other executioner caspases to _____________ them and many cellular targets to produce the apoptotic \_\_\_\_\_\_\_\_\_\_\_\_\_\_.
Activate
Phenotype
37
Initiator or executioner caspases lead to DNA laddering?
Executioner caspases
38
Executioner caspases can target ______________ proteins, including cohesions, cadherins, lamins, spectrin, troponin, etc.
Structural
39
Regulators of transcription and translation are cellular targets for ___________________ caspases.
Executioner caspases
40
\_\_\_\_\_\_\_\_\_\_\_\_\_\_ and signaling molecules are targetted by executioner caspases.
Kinases
41
What are three primary targets of executioner caspases?
Structural targets, regulators of transcription and translation, and kinases and signaling molecules
42
What inhibits executioner (and initiator) caspases?
Inhibitor of apoptosis proteins (IAPs)
43
What does IAP stand for?
Inhibitors of apoptosis proteins (IAPs)
44
Why are initatiors of apoptosis proteins (IAPs) important?
They inhibit caspases and function as a "safety net" in case of accidental activation of apoptosis
45
The extrinsic pathway of apoptosis requires the targetted cell has __________ receptors.
Death receptors
46
The two most common ligands for death receptors are __________________ and \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
Fas ligands
Tumor necrosis factors (TNF-alpha)
47
Death receptors contain a cytosolic ______________ domain.
Cytoplasmic death domain
48
Death receptors form \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_, trimerizing after ligand binding.
Homotrimers
49
What are two common death receptors?
Fas death receptor
TNF-alpha death receptor
50
Death receptors recruit adaptor proteins on the cytosolic side called FADDs, which stands for \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
Fas associated protein with death domain
51
FADD (Fas associated protein with death domain) possess two domains. What are they?
1. A death domain that binds the receptor
2. A death effector domain (DED) that recruits and activates initiator caspases 8 and 9
52
What does DED stand for?
Death effector domain
53
The \_\_\_\_\_\_\_\_\_domain of a receptor interacts with the ________ domain of adaptor protein.
Death domain
Death domain
54
A death effector domain (DED) interact with initiator procaspases, which also have \_\_\_\_\_\_\_\_\_\_\_\_\_.
DED (death effector domains)
55
The Fas and/or TNF receptor binds its adaptor protein ___________________________ (FADD) and together form the ________________________ (DISC).
**F**as **a**ssociated protein with **d**eath **d**omain
**D**eath-**i**nducing **s**ignaling **c**omplex
56
What does DISC stand for?
Death-inducing signaling complex
57
What do we mean by homotypic binding?
In the case of death receptors, both the death receptor and the adaptor protein contain death domains
58
There is another type of TNF receptor that assembles a complex of three parts: \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_, \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_,and \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
TNF receptor associated protein with death domain and (DED) (TRADD)
TNF receptor associated factor (TRAF)
FADD, which recruits and activates procaspase 8
59
Fas and most TNF receptors simply recruit _________________ (FADD) upon ligand binding, which then recruits initiator procaspases 8 and 9.
Fas associated protein with death domain
60
There is another type of TNF receptor that assembles a complex of three parts to initiate the extrinsic pathway of apoptosis: \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_, \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_, and \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
TNF receptor associated protein with dead domain (and DED) (TRADD), an adaptor protein
TNF receptor associated factor (TRAF)
Fas associated protein with death domain (FADD), which ultimately recruits procaspase 8
61
TRADD refers to \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
TNF receptor associated protein with death domain (and DED)
62
TRAF refers to \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
TNF receptor associated factor
63
FADD refers to \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
Fas associated protein with death domain
64
The TNF receptor recruits the adaptor protein \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_, which then recruits procaspase 8 to the site.
Fas associated protein with death domain
65
In immune cells, the TNF receptor binding its ligand is "pro-life" as opposed to "\_\_\_\_\_\_\_\_\_\_." Ligand binding recruits TRAF (\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_) that forms a __________________________________ scaffold and leads to ______________ activation, which then activates immune cells and leads to the ______________ response.
Pro-death
TNF receptor associated factor
Polyubiquitin
NF-kappaB
Inflammatory
66
NF-kappaB is a ______________ factor that triggers upregulation of genes involved in the ___________________ response.
Transcription factor
Inflammatory
67
In cell *except* immune cells, TNF receptor binding leads to \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
Apoptosis
68
NF-kappaB is a ________________ factor and increases expression of a protein called \_\_\_\_\_\_\_\_\_\_\_\_\_\_.
c-FLIP
69
c-FLIP is a protein that is upregulated by \_\_\_\_\_\_\_\_\_\_\_\_\_.
NF-kappaB
70
How does c-FLIp function as a "pro-life" transcription factor?
Because it possesses a death effector domain (DED) that competes with procaspase 8 for binding to FADD (Fas associated protein with death domain); binding of c-FLIP to FADD, instead of procaspase 8, inhibits the apoptotic pathway
71
What happens when c-FLIP outcompetes procaspase 8 for FADD binding?
The apoptotic pathway is inhibited
72
What is DED?
Death effector domain
73
Which orgenlle is most important to the intrinsic pathway of apoptosis?
The mitochondria
74
What does the instrinsic pathway of apoptosis require?
The release of proteins from the mitochondrial intermembrane space, specifically cytochrome C
75
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ is the most critical protein released from the mitochondrial intermembrane space in the ______________ pathway of apoptosis.
Cytochrome C
76
Why can cytochrome C leave the mitochondrial intermembrane space during apoptosis?
Because of **mitochondrail outer membrane permeabilization** (MOMP)
77
What does MOMP stand for?
Mitochondrial outer membrane permeabilization
78
What proteins function in mitochondrial outer membrane permeabilization (MOMP)?
Bcl2 proteins
79
What does Bcl2 stand for?
B-cell lymphona (2)
80
Proteins that mediate MOMP are a family of proteins called \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
Bcl2 (B-cell lymphoma 2)
81
Anti-apoptotic ______ proteins prevent cells from engaging in MOMP. These inculde \_\_\_\_\_\_, Bcl-xL, Bcl-W, and Mcl-1.
Bcl-2
82
There are three types of proteins in the Bcl2 family: \_\_\_\_\_-apoptotic, \_\_\_\_\_-apoptotic, and \_\_\_\_-only.
Anti-apoptotic (Bcl-2, Bcl-xL, Bcl-W, Mcl-1)
Pro-apoptotic (Bax, Bak, Bok)
BH3-only (Bad, Bim, Bid, Puma)
83
What Blc2 proteins are pro-apoptotic?
Bax, Bak, and Bok
84
Which Bcl2 proteins are anti-apoptotic?
Bcl-2, Bcl-xL, Bcl-W, Mcl-1
85
Which Bcl2 proteins are BH3-only?
Bid, Bim, Bad, Puma
86
Which group of Bcl2 proteins can be inserted into the outer mitochondrial membrane and result in MOMP?
Bax and Bak or the pro-apoptotic group
87
To what does BH refer in BH3-only proteins of the Bcl2 family?
"Bcl2 homology domain"
88
What does Bax stand for?
Bcl-2 associated protein X
89
What does Bak stand for?
Bcl2 associated killer protein
90
Mitochondrial outer membrane permeabilization (MOMP) is inhibited by which anti-apoptotic proteins?
Bcl-2, Bcl-xL, etc.
91
How do Bcl-2 and Bcl-xL inhibit MOMP?
By binding Bcl2 effector proteins and preventing pro-apoptotic factors Bax and Bak from binding and asssembling
92
Which Bcl2 proteins are responsible for activating MOMP?
Bax and Bak
93
Which proteins are required for activation of Bax and Bak and therefore MOMP?
The BH3-only proteins: Bid, Bim, Bad, PUMA
94
\_\_\_\_\_\_, \_\_\_\_\_\_\_\_\_\_\_, \_\_\_\_\_\_\_\_\_\_\_\_, and _______________ are BH3-only proteins of the Bcl2 family and are required for assembly of Bax and Bak.
Bid, Bad, Bim, PUMA
95
What is the mechanism for mitochondrial outer membrane permeabilization (MOMP)?
Bax and Bak dimerize and oligomerize in the outer mitochondrial memb rane, forming channels or pores that allow cytochrome C to escape
96
\_\_\_\_\_\_\_\_\_ and Bak can form homodimers; they can sometimes for \_\_\_\_\_\_\_\_\_\_\_\_\_\_.
Bax
Heterodimers
97
Once dimerized, Bax and Bak form \_\_\_\_\_\_\_\_\_\_\_\_\_.
Oligomers
98
Oligomerization is required for the process of ________________ in the mitochondria.
Mitochondrial outer membrane permeabilization (MOMP)
99
Bak is constitutively \_\_\_\_\_\_\_\_\_\_\_\_\_\_-bound.
Membrane-bound
100
Activation of Bak in the mitochondrial outer member causes its \_\_-\_\_\_\_\_\_ to extend, and the _________________ side of the \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_core to latch and collapse into the membrane, thererby separating the two parts of Bak.
C-terminus
Hydrophobic
Amphipathic
101
What does this picture refer to?
Activation of Bak in the outer mitochondrial membrane
102
Which alpha helix of Bak is embedded in the membrane?
Alpha helix 9
103
Which alpha helices constitute the core of Bak?
Alpha helices 3, 4 and 5
104
Which alpha helix of Bak contains the BH3 domain?
Alpha helix 2
105
Which alpha helices form the latch of Bak?
Alpha helices 6, 7, and 8
106
How does Bak dimerization occur?
The exposed BH3 domain of the alpha 2 helix binds to the hydrophobic groove of another activated Bak molecule
107
The exposed _____ domain of Bak's alpha 2 helix binds to the hydrophobic groove of another activated Bak molecule, facilitating \_\_\_\_\_\_\_\_\_\_\_\_.
BH3 domain
Dimerization
108
\_\_\_\_\_\_ shuttles between the cytosol and the membrane, and when in the membrane, it undergoes a _______________ change and dimerizes.
Bax
Conformational change
109
Is it Bak or Bax that shuttles between the cytosol and membrane?
Bax
110
There are several theories regarding how pores form: (1) Bax and Bak oligomers for protein channel pores; (2) Bax and Bak modulate pre-existing channels; and (3) Bax and Bak facilitate formation of lipidic or toroidal pores. Which of the three theories is most supported by current research?
The third model
111
Some ___________ toxins have been shown to produce ______ pores.
Bacterial
Lipidic
112
It is hypothesized that these proteins exert a \_\_\_\_\_\_\_\_-like action that induces curvature of the membrane and ultimately formation of the pore.
Detergent
113
The core and latch domains of ______ and ______ share structural features with the _________ toxins and antibacterial peptides known to form _____________ pores.
Bax
Bak
Bacterial toxins
Lipidic pores
114
Bax and Bak share structural similarities to what proteins, which supports the theory that lipidic pores are formed and facilitate MOMP?
Bacterial toxins
Antibacterial peptides
115
In the _____________ model of pore formation, the ________________ latch may slide into a nascent pore to line and stabilize it and then the amphipathic core dimer lines the pore, generating ______________________ alpha9 helices.
Clamp
Amphipathic
Antiparallel
116
Explain the clamp model of pore formation.
The ampiphatic latch may slide into a nascent pore, lining and stabilizing it. Then the amphipathic core dimer lines the pore, generating antiparallel alpha-9 helices
117
118
What type of microscopy confirms the lipidic pore model of MOMP?
Atomic force microscopy
119
Upon its release, cytochrome C binds \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
Apaf-1 (apoptotic protease activating factor 1)
120
What does Apaf-1 mean?
Apoptotic protease activating factor 1
121
What is an apoptosome?
A wheel-shaped heptamer that recurits initiator procaspase 9 to the mitochondrial membrane
122
What domains bind the apoptosome together?
CARD domains
| (Caspase recruitment domains)
123
Cytochrome C binds __________ and recruit initiator _____________ 9, forming the apoptosome.
Apoptotic prootease activating factor 1 (Apaf-1)
Procaspase 9
124
What is a CARD?
A caspase recruitment domain
125
Procaspase 9 and cytochrome C bind via ____________ interactions.
Caspase recruitment domains (CARD)
126
What are IAPs?
Inhibitors of apoptosis proteins
127
What happens as cytochrome C is released?
So too are other proteins that bind IAPs or inhibitors of apoptosis proteins
128
As cytochrome C is released, so are other proteins that can bind \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_, which prevents them from inhibiting \_\_\_\_\_\_\_\_\_\_\_\_\_.
Inhibitors of apoptosis proteins (IAPs)
Apoptosis
129
Which two other proteins are released from the mitochondria alongside cytochrome C?
Smac/DIABLO
OMI
130
To what do IAPs normally interact?
Inhibitors of apoptosis proteins (IAPs) usually interact with caspases, thereby inhibiting apoptosis
