Week 5- Cell Death- Holy

Question 1

3 types of cell death

Answer 1

1) Apoptosis
2) Autophagic
3) Neorosis

Question 2

Necrosis

Answer 2

• largely unregulated
• cells “blow up.”
• Associated with inflammation (due to release of cytoplasm)
• cells die due to traumatic injury/insult
• very rapid cell death

Question 3

Autophagy

Answer 3

• thought of as survival, rather than cell death

- highly regulated

Question 4

Apotosis

Answer 4

• largely regulated
• “programmed cell death”
• visually indicated by condensation of chromatin
• plays important role in sculpting the body of the embryo (digit formation, maturation of the immune system, etc)
• cell displays “blebbing”

Question 5

What are caspases?

Answer 5

a set of proteases used in cell destruction

• caspases are kept inactive until cell decides it needs to die
• can activate by cleaving off inhibitory proteins (ex activating DNase to chop up DNA)

Question 6

MOMP

Answer 6

mitochondrial outer membrane permeabilization

• regulated by Bcl2 family
• more MOMP = more cell death

Question 7

Bcl2

Answer 7

inhibit MOMP ⇒ more cell life

blocks beclin-1 (which promotes autophagy) thus inhibits autophagy

PLAYS ROLE IN BLOCKING BOTH AUTOPHAGY AND APOPTOSIS

Question 8

Bax and Bak (from the same Bcl-2 family)

Answer 8

activate MOMP ⇒ more cell death

Question 9

What are the major pathways that regulate and execute apoptosis

Answer 9

the extrinsic and intrinsic pathway

Question 10

Compare extrinsic and intrinsic pathways of apoptosis

Answer 10

• extrinsic- involves signaling molecules and plasma membrane receptors
• plasma membrane interacts with receptors of active capase 8
• intrinsic- involves damage or stress which is transmitted to the mitochondria
• interacts with capase 9

Question 11

Which type of cell death is associated with inflammation?

Answer 11

necrosis: Associated with inflammation (due to release of cytoplasm)

Question 12

What are the major functions of apoptosis and autophagy?

Answer 12

major players in cell survival/cell death pathways

Question 13

extrinsic pathway

Answer 13

apoptotic ligands (FAS and TRAIL) trimerize ==> bind to approrptiate "death receptor"
==> all of the bindings trimerize ==> form DISC  ==> activates initiator caspases (like caspase 8) ==> caspases activate other caspases (effector caspases) ==> caspase cascade destroys nuclear proteins, cytoskeleton, etc ==> cell death

Question 14

intrinsic pathway

Answer 14

mito membrane gets perturbed ==> promote MOMP ==> pores in outer membrane open ==> release molecules to kill cell (Cyt C, Smac/DIABLO, AIF) ==> released Cyt C associates with Apaf1 ==> form apoptosome ==> activates initiator caspases (like caspase 9) ==> caspases activate other caspases ==> eventual cell death

Question 15

apoptosome

Answer 15

when released Cyt C associates with Apaf1

can go and activate initiator caspses

Question 16

DISC

Answer 16

when a bunch of ligand bound death domains bind together

-can go and activate initiator caspases

Question 17

To further regulate apoptosis cells produce:

Answer 17

1) IAPs: inhibitors of apoptosis proteins; bind to caspases and directly inhibit their proteolytic activity
- these in turn can inhibit themselves; done by Smac/Diablo

2) AIF- apoptosis inducing factor- nuclease that is released by MOMP that can enter the nuclease and cleave DNA ⇒ cell death without caspase activity

Question 18

how are the extrinsic and intrinsic pathways coupled together

Answer 18

Bcl2 family member Bid serves as a link b/t the 2

-DISC cleaves and activates Bid ⇒tBid ⇒ go to mito and activate Bax ⇒ activate MOMP

Question 19

how are cell division factors involved in cell death

Answer 19

if cell is going through cell cycle too much ⇒ excessive Myc production⇒ produces Arf ⇒ Arf binds to Mdm2 ⇒ this doesn’t allow Mdm2 to bind to p53 ⇒ now active p53 can go and start cell apoptosis

Question 20

BH3 proteins

Answer 20

proteins that are pro-apoptotic (pro death)

-work by inhibiting BCL-2 which is a anti-apoptotic protein

Question 21

2 ways for a cell to survive

Answer 21

1) increase in Bcl2 production
2) inactivation of BH3/BAD

1) survival factor binds to receptor ⇒ increase in gene expression ⇒ increase in Bcl2 ⇒ inhibit Bax ⇒ have free Bcl2 ⇒ apoptosis blocked!
2) survival factor binds to receptor ⇒ kinases phosphorylze BH3/BAD ⇒ BH3/BAD cant bind to Bcl2 ⇒ free Bcl2 ⇒ apoptosis blocked

Question 22

major regulator of autophagy

Answer 22

mTOR

Question 23

what is mTOR

what activates it

what inhibits it

Answer 23

mTOR- inhibits autophagy; says everything in the cell is ok we don’t need to kill it

insulin, growth factors, etc activate mTOR bcause those are things that show the cell is working correctly

DNA damage, stress, low energy inhibit mTOR so autophagy can do its thing and try to fix the cell to let it survive

Question 24

AMPK

Answer 24

when activated (by DNA stress, low energy, etc) block mTOR thus activate autophagy

Question 25

Beclin-1

what can inhibit it

Answer 25

initiates autophaphy without going through mTOR

Bcl2 inhibits Beclin-1 thus inhibits autophagy

Question 26

What morphological features characterize apoptosis and autophagy?

Answer 26

Morphological features in apoptosis → blebbing via actin activity, apoptotic bodies
Morphological features in autophagy → autophagosome made by ER proteins

Question 27

IAP

Answer 27

inhibits caspase 9 = (-) apoptosis

Question 28

Smac/Diablo

Answer 28

inhibits IAP = (+) apoptosis

Question 29

Arf

Answer 29

produced in presence of high levels of Myc, binds and inhibits Mdm2 allowing active p53 to bind to DNA = halt cell division, (+) apoptosis

Question 30

Reverse Warburg Effect

Answer 30

tumor cells induce fibroblasts to enter autophagy, which releases nutrients like lactate and ketones → ketones and lactate are taken up by tumor cell and used for electron transport in tumor cell leading to proliferation