Lecture 11- Programmed cell death

Question 1

What is programmed cell death essential in?

Answer 1

1. embryonic development
2. metamorphosis
3. immune system function
4. cleanly removing excess, old, damaged, abnormal, or malfunctioning cells

Question 2

what does phosphorylated p53 bind to?

Answer 2

phosphorylated p53 is active and binds to the regulatory region of the p21gene. p21 mRNA is made and then the p21 protein (CDK inhibitor protein).
causes apoptosis.

Question 3

apoptosis

Answer 3

highly regulated, reproducible form of programmed cell death

Question 4

necrosis

Answer 4

accidental, uncontrolled cell death and can cause inflammation

Question 5

what does apoptosis do?

Answer 5

it carefully dismantles the cell and signals for its removal by engulment

Question 6

what do changes in apoptosis include?

Answer 6

1. cell shape changes and shrinkage
2. cytoskeleton disassembly
3. decreased cell adhesion
4. DNA fragmentation
5. surface lipid changes
6. cell removal by engulfment

Question 7

what protease triggers apoptosis?

Answer 7

caspase

Question 8

how are caspases synthesized?

Answer 8

as inactivae procaspases

Question 9

how are active caspase dimers formed ?

Answer 9

signals initiate caspase cleavage to form active caspase dimers

Question 10

caspase cascade

Answer 10

some caspases can cleave and activate other caspases to create and amplified caspase cascade

Question 11

how do caspases trigger apoptosis?

Answer 11

they cleave specific target proteins

Question 12

which caspases are initiator caspases

Answer 12

caspase 8 and caspase 9

Question 13

initiator caspases

Answer 13

cleaved and activated in response to apoptotic signals

Question 14

which caspases are executioner caspases

Answer 14

caspase 3, 6 and 7

Question 15

executioner caspases

Answer 15

cleaved and activated by initiator caspases creating a caspase cascade

Question 16

what do executioner caspases do?

Answer 16

the cleave and target proteins in the cell to initiate apoptosis

Question 17

what does the caspase target to get cell shape change and shrinkage

Answer 17

cell-cell adhesion proteins

Question 18

what does the caspase target to get DNA fragmentation

Answer 18

breakdown of nuclear lamins
activation of DNA endonucleases

Question 19

what does the caspase target to get cytoskeleton disassembly

Answer 19

alter actin regulatng proteins

Question 20

what does the caspase target to get surface lipid changes

Answer 20

lipid distibution proteins
1. flippase inactivation
2. scramblase activation

Question 21

how do executioner caspases indirectly cause DNA breakdown?

Answer 21

an inactive CAD is bound to the inhibitor of CAD
the executioner3 cascade cleaves inhibitor of CAD, activating CAD
active CAD causes cleavage of DNA between nucleosomes

Question 22

what do healthy cells have

Answer 22

active flippase, inactive scramblase

Question 23

what happens to flippase and scramblase in apoptotic cells

Answer 23

1. caspase cleaves flippase to inactivate it
2. caspase cleaves scramblase activating it (more lipids to outer layer)

Question 24

what pathways can apoptosis be triggered by?

Answer 24

extrinsic and intrinsic pathways

Question 25

extrinsic pathway

Answer 25

depends on cell surface receptors binding to an extracellular signal molecule to activate executionar caspases

Question 26

intrinsic pathway

Answer 26

depends on intracellular receptors - depends on cytochrome C

Question 27

components of extrinsic apoptosis pathway

Answer 27

caspase 8, FADD adaptor protein, Fas death receptor, killer lymphocytes

Question 28

domain in caspase 8

Answer 28

death effector domain

Question 29

domains in FADD adaptor protein

Answer 29

death effector domain and death domain

Question 30

domain in Fas death receptor

Answer 30

death domain

Question 31

what do killer lymphocytes express

Answer 31

cell surface Fas ligands

Question 32

DISC - death inducing signalling complex

Answer 32

killer lymphocyte with Fas ligand binds to the Fas receptor the death domain in Fas receptor is activated the death domain in Fas recptor binds and activates the death domain in FADD adaptor protein the death effector protein in FADD is active and it binds to the death effector protein in caspase 8 activating it

Question 33

what can healthy cells express to evade extrinsic apoptosis pathway signals

Answer 33

decoy receptors

Question 34

what do decoy receptors lack

Answer 34

intracellular death domains

Question 35

how do decoy receptors help healthy cells to stay alive

Answer 35

When Fas ligand binds to decoy receptor, no DISC assembles, so apoptosis is not triggered

Question 36

what does intrinsic apoptosis pathway depend on

Answer 36

Apaf1 and cytochrome C

Question 37

how does intrinsic apoptosis work

Answer 37

cytochrome C binds to Apaf this exposes the CARD domain and the oligomerization domain of Apaf1.

Question 38

what domains on Apaf1 are exposed when cytochrome C binds to it

Answer 38

CARD domain and oligomerization domain

Question 39

how does cytochrome C release activate the intrinsic apoptosis pathway ?

Answer 39

1. cytochrome C is released from the intermembrane space 2. it binds to Apaf 1, CARD domain and oligomerization domain are exposed 3. oligomerization of Apaf1 takes place (apoptosome without caspase) 4. there is recruitment of caspase 9 monomers to apoptosome and caspase 9 activation by dimerization 5. cleavage and activation of executioner caspases by activated caspase 9 dimers

Question 40

what releases cytochrome C

Answer 40

mitochondrial outer membrane permeabilization cyctochrome C cannot usually cross outer membrane

Question 41

how do channels in the outer mitochondrial membrane form

Answer 41

apoptotic stimuli trigger Bak and Bax proteins to form a channel in the outer mitochondrial membrane

Question 42

what do bak and bax channels promote

Answer 42

mitochondrial outer membrane permeabilization

Question 43

what bcl2 family members are similar to bac and bax

Answer 43

bcl2 and bcIxL

Question 44

Bcl2 and BclxL action

Answer 44

they bind bac and bax preventing them from forming channels they block MOMP so they are considered anti-apoptotic proteins

Question 45

BcI1 family proteins that can promote MOMP

Answer 45

Bad

Question 46

explain the action of Bad

Answer 46

Bad binds to BcI2 and BcIxL Bad promotes MOMP and is a pro-apoptotic protein

Question 47

IAPs

Answer 47

they are inhibitors of apoptosis

Question 48

IAP that can block both initiator and executioner caspases

Answer 48

XIAP

Question 49

anti IAP proteins

Answer 49

usually in the mitochondrial intermembrane apce they are released with cytochrome C when MOMP is triggered they inhibit XIAP, allowing the caspase cascade to trigger apoptosis

Question 50

examples of anti IAP proteins

Answer 50

Omi and Smac

Question 51

Survival factors

Answer 51

Many cells will undergo apoptosis if they are not supplied with survival factors cells that leave their correct environment are no longer protected by survival factors

Question 52

what limited availibility of survival factors do

Answer 52

regulate cell numbers

Question 53

cascade initiated by survival factors to activate anti apoptotic proteins

Answer 53

BcI2 transcription increases BcI2 and BcIxL block Bak/Bax from forming a channel in the mitochondrial outer membrane MOMP I blocked, apoptosis does not occur

Question 54

cascade initiated by survival factors to inactivate pro-apoptotic proteins

Answer 54

Akt kinas is activated and phosphorylated bad BAD is inactive and cant bind to BcI2 and BcIxL they bind Bax and Bax, MOMP not occurring, apoptosis does not proceed

Question 55

inappropraite cell death leading to disease

Answer 55

1. cancer cells display properties that should makr them for apoptosis (changes to cell adhesion, DNA damage, survival outside their usually environment)

Question 56

how do cancer cells grow and proliferate

Answer 56

must escape apoptosis