Chapter 16 Flashcards
1
Q
The process of eliminating unwanted cells during embryogenesis, metamorphosis, and tissue turnover
A
programmed cell death
2
Q
Programmed cell death is the process of eliminating unwanted cells during what 3 events?
A
embryogenesis, metamorphosis, and tissue turnover
3
Q
Paw that has an interdigital web
A
embryonic mouse paw
4
Q
Paw that has no interdigital web removed
A
mature mouse paw
5
Q
Cell death
A
apoptosis
6
Q
What are the cell structure changes that accompany apoptosis?
A
a. compaction, blebbing of the plasma membrane
b. fragmentation of the nucleus and cell
c. condensing of the chromatin
7
Q
What happens to DNA during apoptosis?
A
fragmented into a ladder
8
Q
Apoptosis does not have what response?
A
no inflammatory response
9
Q
Apoptosis can be triggered by (6)
A
a. DNA damage
b. heat or cold shock
c. targeting by cytotoxic lymphocytes
d. various drugs
e. withdrawal of essential growth factors
f. other stressed
10
Q
Apoptosis is important for removing what?
A
tumorigenic cells
11
Q
What tumor suppressor can trigger apoptosis?
A
p53
12
Q
Cells that die via ____ swell, burst open, invoke an inflammatory response, and do not display chromatin condensation?
A
necrosis
13
Q
Necrosis is cell death after
A
injury
14
Q
apoptosis is what cell death
A
programmed cell death
15
Q
3 steps of necrosis
A
- cell swells
- cell bursts
- inflammatory response
16
Q
3 steps of apoptosis
A
- nucleus fragments
- cell fragments
- engulfment of fragments: no inflammatory response
17
Q
Caspases
A
cysteine aspartate-specific protease
18
Q
Caspases are available initially as
A
symogens
19
Q
How are zygomens activate?
A
must be proteolytically cleaved
20
Q
What are the 3 main types of caspases?
A
a. executioner
b. initiator
c. inflammatory
21
Q
2 executioner caspases
A
caspase-3 and caspase-7
22
Q
What are responsible for cleaving many proteins to effect apoptosis?
A
executioner caspases
23
Q
Executioner caspases are responsible for cleaving many proteins at where?
A
recognition sites of 4 aa residues with couple of AA residues
24
Q
3 example substrates for executioner caspases
A
a. CAD
b. ROCK-1
c. Gelsolin
25
CAD
caspase-dependent DNase
26
What is CAD responsible for what during apoptosis?
DNA fragmentation
27
CAD exists as a complex with what?
an inhibitor iCAD
28
iCAD is cleaved by
an executioner caspase
29
When iCAD is cleaved by an executioner caspase, CAD is active and digests ____ resulting in?
DNA between the nucleosomes; ladder of DNA fragments
30
What is a myosin-light chain kinase?
ROCK-1
31
How is ROCK-1 activated?
by cleaving with an executioner caspase
32
How is Gelsolin activated?
cleaved and activated by an executioner caspase
33
Why is gelsolin named gelsolin?
because it helps regulate actin by turning the gel of cross-linked actin into a sol
34
Role of gelsolin
role in the formation of these podosomes
35
What 2 affect changes in the cytoskeleton, initiating the blebbing associated with apoptosis?
ROCK-1 and gelsolin
36
Zymogen forms of executioner caspases are known as?
procaspases
37
How are procaspases activated?
by clasave at an Asp
38
Activation of procaspases brings _____ region into proximity with the _____ region
substrate-binding; catalytic cys-his-dimer
39
What is one protease that can catalytically activate executioner caspase?
Granzyme B
40
Granazyme B is in the granules of cytotoxic lymphocytes, both __ and ____.
cytotxic T cell (Tc); natural killer (NK) cells
41
When is granzyme B released from the granules?
when the cytotoxic cell targets another cell, enters the target cell, and activates executioner caspases to cause apoptosis
42
What cleaves and activates caspase-6?
caspases-3 and -7
43
What cleaves and activates the executioner caspases?
initiator caspases
44
What known initiator caspases in mammals preexist as inactive monomers?
initiator caspases-2, -8, -9, and -10
45
Mechanism of activation of initiator caspases is known as
induced proximity
46
What is the mechanism for induced proximity?
initiator caspases are activated upon dimerization and activated dimer cleaves and activates executioner procaspases
47
Initiator caspases contain large prodomains with protein-protein interaction motifs known as?
death folds
48
Death folds interact with ____ to ____ them or their partner in a dimer) in what manner?
adaptor proteins; activate; like-like manner
49
What are 4 examples of death folds?
a. DEDs
b. CARDs
c. DD
d. PYR
50
DEDs
death effector domains
51
CARDs
caspase recruitment domains
52
DD
death domains
53
PYR
pyrin domains
54
IAPs
inhibitors of apoptosis proteins
55
XIAP
X-linked IAP
56
XIAP inhibits what?
initiator caspase-9
executioner caspases -3 and -7
57
2 IAP domains
BIR
RING finger domain
58
BIR
Baculovirus IAP repeats
59
If an IAP has RING finger domain, it functions as what?
Ub-3-ligase
60
What is the first caspase identified?
caspase-1
61
Caspase-1 is required for what?
processing/secretion of cytokine IL-1beta (interleukin-1beta)
62
Caspase-1 is also known as?
ICE (IL-1beta converting enzyme)
63
ICE
interleukin-1beta converting enzyme
64
Caspase-1 requires ___ to activate it
caspase-5 + 1 adaptors
65
What are the 2 apoptotic pathways?
a. death receptor pathway
b. mitochondrial pathway
66
Which pathway is extrinsic?
death receptor pathway
67
Which pathways is intrinsic?
mitochondrial pathway
68
Both death receptor and mitochondrial pathway converge to activate what 2?
a. initiator caspases
b. executioner caspases
69
Initiator caspases activate via?
induced proximity
70
There is ____ between death receptor and mitochondrial pathway
cross-talk
71
TNFR
tumor necrosis factor receptor
72
TNFR includes
death receptors (DR) which are trimeric
73
What are 3 examples of death receptors?
a. TNFR 1
b. Fas
c. TRAIL receptor
74
Death receptors share what?
death domain (DD)
75
4 Examples of death folds
a. DD
b. CARD
c. DED
d. PYR
76
Death domain in a death receptor interacts with ____
death domains in adaptor molecules
77
DR trimers are cross-linked by?
ligand binding
78
Death domains of Fas and TRAIL receptors bind to ____ via ____.
adaptor protein FADD (Fas-associated DD); DDs
79
FADD
Fas-associated DD
80
FADD has
DEDs
81
DEDs of FADD bind to DEDs in what?
prodomain of caspase-8 monomers
82
Proaspase-8 monomers form what?
dimers
83
What causes activation of initiator caspases?
induced proximity
84
DISC
death-inducing signaling complex
85
DISC is made of
DR, FADD, and caspase-8 complex
86
DISC activates what 3 that leads to apoptosis?
executioner caspases-3, -6, and -7
87
TNFR1 activates a pathway to lead to activation of what?
executioner caspase
88
TNFR1 can bind to what?
TRAFs (TNF receptor associated factors)
89
TRAFs
TNF receptor associated factor
90
TRAFs can activate which transcription factor?
NF-kB (nuclear factor-kB)
91
NF-kB
nuclear factor-kB
92
Some proteins expressed by NF-kB prevents what?
DISC formation and caspase-8 activation
93
Expression of NF-kB leads to _____ instead of _____.
inflammation; apoptosis
94
Most forms of vertebrate apoptosis are triggered via ____.
mitochondrial pathway
95
MOMP
mitochondrial outer membrane permeability
96
What is one of the soluble proteins from the intermembrane space released into the cytosol?
holocytochrome c
97
Role of holocytochrome c in mitochondria
transfers electrons from complex III to complex IV in ETS
98
Role of holocytochrome c in the cytosol
helps activate caspases
99
What domains do Bcl-2 family proteins share?
up to four Bcl-2 homology (BH) domains
100
BH domain
Bcl-2 homology domain
101
3 subfamilies of Bcl-2 proteins
a. anti-apoptotic
b. pro-apoptotic 'multi-domain'
c. pro-apoptotoic BH2-only proteins
102
Anti-apoptotic subfamily of Bcl-2 proteins possess
BH1-3 and BH-4
103
Function of Anti-apopototic
prevents MOMP
104
Examples of Anti-apoptotic subfamily
Bcl-2
Bcl-xL
105
Pro-apoptotic 'multi-domain' subfamily of Bcl-2 proteins possess
BH1-3
106
Examples of pro-apoptotic 'multi-domain'
Bax
Bak
107
Examples of pro-apototic BH3-only proteins
Bid
Bim
108
Bax and Bak are responsible for?
MOMP
109
What proteins form the pores through which proteins escape the mitochondrial and enter the cytosol?
Bax and Bak
110
Bax or Bak are induced to oligomerize in the mitochondrial membrane in the presence of what?
pro-apoptotic BH3-only proteins like Bid
111
Bax-Bak DKO cells
double-knock-out
lack both of these proteins
112
What happens to Bax-Bak DKO cells when deprived of growth factors?
do not undergo apoptosis but rather undergo autophagy
113
What does autophagy mean?
self-eating
114
Bax-Bak DKO cells sustain themselves by?
catabolizing intracellular components
115
How do normal cells use Bax-Bak?
to engage the mitochondrial pathway of apoptosis when deprived of growth factors
116
Anti-apoptotic members of the Bcl-2 family act by binding to ___ to prevent their function
activator proteins or active forms of Bax and Bak
117
Anti-apoptotic members of the Bcl-2 family binding to activator proteins or active forms of Bax and Bak result in
preventing MOMP and apoptosis
118
Other members of the BH3-only subfamily promote apoptosis by
blocking the function of antiapoptotic Bcl-2 family members
119
BH3-only subfamily are what?
stress sensors
120
BH3-only subfamily act as
de-repressors/sensitizers
121
BH3-only subfamily regulated at levels of_____, ____, ____, and ____
transcription; protein stabilization; protein-protein interactions; modifications
122
MOMP leads to release of ____ in cytosol
holocytochrome c
123
holocytochrome c in cytosol binds to what?
APAF-1
124
APAF-1
apoptotic protein activating factor-1
125
How does APAF-1 expose an oligomerization domain?
APAF-1 undergoes a conformation change, binds to dATP, and undergoes a second conformation change
126
Exposing of oligomerization domain by APAF-1 leads to what complex?
7 APAF-1 complex = apoptosome
127
Apoptosome has exposed ____ in the center
CARD domains
128
CARD domains of apoptosome binds to what?
CARD domains of an initiator caspase-9
129
Active initiator caspase-9 activates what?
executioner caspase-3 and -7
130
Activation of executioner caspase-3 and -7 leads to what?
apoptosis
131
What is translated in cytosol and imported into the mitochondrion?
apocytochrome c
132
What activates APAF-1 and what does not?
holocytochrome c activates APAF-1 but apocytochrome does not activate APAF-1
133
What interfere with caspase activation?
IAPs
134
XIAP function (2)
a. inhibits inhibitor caspase-9 on the apoptosome
b. binds and inhibits executioner capsase-3 and -7
135
Smac is known as
DIABLO
136
What proteins are released from mitochondria upon MOMP?
smac and omi
137
Function of smac and omi
antagonize XIAP to allow caspase activation
138
What is the N-terminus of smac and omi?
AVPI motif
139
Function of AVPI motif
inhibits XIAP
140
How is AVPI motif generated?
after removal of the mito-targeting sequence upon translocation of the protein into the mitochondrial membrane space after they were translated in the cytosol
141
Death receptor pathway activates
initiator caspase-8
142
Initiator caspase-8 cleave and activate what 3?
executioner caspase-3 and -7, and Bid
143
Cleaving and activating of Bid by initiator caspase-8 cause what?
MOMP and apoptosis via the mitochondrial pathway
144
What 2 other protease can cleave and activate Bid?
cathepsins and calpains
145
What are cathepsins?
lysosomal proteases
146
What are calpains?
non-lysosomal calcium-dependent proteases
147
Following cytotoxic lymphocyte granzyme B release, what is a preferred mechanism of apoptosis induction?
Bid-mediated MOMP
148
What death occurs without chromatin condensation?
Caspase-independent cell death
149
Caspase-independent cell death involve a slow loss of what function?
mitochondrial function
150
Caspase-independent cell death may be due to what actions of proteins?
proteins released from mitochondria, other than those that involve caspases
151
What are 3 proteins to antagonize IAP function?
Reaper, Grim, and Sickle
152
What does Reaper, Grim, and Sickle carry?
motif related to the AVPI motif of Smac and Omi
153
Clearance of apoptotic celss occur by what?
phagocytosis
154
What clears apoptotic cells by phagocytosis?
macrophage or dendritic cells
155
Apoptotic cells generates signals to _____
solicit its engulfment
156
What are 3 signals generated by apoptotic cells to solicit its engulfment?
a. find me signals
b. eat me signals
c. discruption of don't eat me signals
157
What is an example of don't eat me signals?
CD31 signal
158
What is an example of eat me signal?
externalization of phosphatidylserine (PS)
159
PS normally found on ___ of plasma membrane.
c-face
160
PS is kept on the c-face of the plasma membrane by what?
by the ATP-dependent flippase type of translocase
161
Flippase type of translocase function
moves PS from non-c-face to c-face
162
What activates scramblase type of translocase?
calcium or caspases
163
Where are scramblases active?
in the SER membrane
164
Function of scramblase type of translocase
randomly flip-flopps phospholipids to even out the growth of the membrane
165
PS on the surface can bind to bridges such as _______
MFG-E8
166
MFG-E8 binds to what?
integrin receptors on phagocytotic cells
167
Example of a find me signal
lysophosphatidylcholine
168
lysophosphatidylcholine is produced by what?
by activated phospholipase A
169
Phospholipase A is activated by what?
executioner caspase
170
How is executioner activated to activate phospholipase A?
by enzymatic cleavage
171
Why do many viruses block apoptosis?
to keep their host alive until sufficient virus is produced and the cell is lysed
172
Some vertebrate viruses prevent what?
apoptosis induced by immune effector cells
173
What virus produce protease inhibitors, serpins?
Pox viruses
174
Function of serpins
blocks granzyme B that blocks caspase 8
175
What is involved with mechanisms of subversion of the mechanisms of the apoptosis?
cancer
176
Tumor suppressor p53 acts in cancer mechanism by
inducing apoptosis in the transformed cell
177
Clearance of apoptotic cells can actively inhibit what?
inflammation and immune responses
178
Function of nitric oxide
signaling molecule for inflammation
179
When phagocytosed by dendritic cells, apoptotic blebs can result in what?
Ag presentation in a manner that induces a state of immune tolerance
180
Lupus
autoimmune disease SLE
181
SLE (lupus) is characterized by what?
auto-AB to intracellular Ag like dsDNA
182
A characteristic feature of lupus
presence of LE bodies (apoptotic cells) in their circulation - not effectively cleared
