Green - Apoptosis

Question 1

Blebbing

Answer 1

Cell shrinks and breaks up into membrane enclosed fragments

Question 2

What is the fate of an apoptic cell?

Answer 2

Recognized and phagocytosed by macrophages and neighboring cells

Question 3

Caspases

Answer 3

Cleave proteins; present as inactive precursors–activated by cleavage by other caspases

Question 4

What are the two types of caspases and what are their roles?

Answer 4

Initiators and Executioners

Initiator caspases activate executioner caspases, which can activate other executioner caspases (cascade)

Question 5

What are the main targets of caspases?

Answer 5

Inhibitor of DNase

Lamins

Cytoskeletal proteins

Inhibitors of apoptosis (Bcl-2, Bcl-xL, FLIP, IAM, XIAP)

Question 6

What are two main pathways for apoptosis?

Answer 6

1. Intrinsic/Stress
2. Extrinsic/Death Receptor

Question 7

What family of proteins determine if apoptosis occurs?

Answer 7

Bcl-2

Both activators and inhibitors

Question 8

Antiapoptotic Proteins

Answer 8

Inhibit apoptosis by sequestering pro-apoptotic proteins

Bcl-2

Bcl-xL

Question 9

Bcl-2

Answer 9

Antiapoptotic

Question 10

Bcl-xL

Answer 10

Antiapoptotic

Question 11

Propaptotic (non mitochondrial)

Answer 11

Bad

Bid

Question 12

Proapoptotic (Mitochondrial Migration)

Answer 12

Bak

Bax

Question 13

How do Bcl-2 proteins interact?

Answer 13

Pro-apoptotic (Bid, Bad) inactivate anti-apoptotic (Bcl-2, Bcl-xL)

Allows other pro-apoptotic (Bax, Bak) to activate apoptosis

Question 14

What can trigger the mitocondrial/intrinsic pathway of apoptosis?

Answer 14

Disruption of electron transport or production of reactive oxygen species

Question 15

If damage to DNA or mitochondria occurs, what results?

Answer 15

1. Cytochrome C moves to cytosol
2. Apaf-1 + ATP + Cytochrome C form Apoptosome
3. Caspase-9 binds, activated

4. Downstream caspases activated (3/7)

Question 16

Death Receptor/Extrinsic Pathway

Answer 16

Immune System

Fas Receptor

Question 17

What is the process of the Extrinsic or Death Receptor pathway?

Answer 17

1. Fas-Ligand (FasL) binds Fas receptor on another cell
2. Fas trimerization
3. FADD binds via Death Domains on Fas

4. Caspase 8 binds at Death Effector Domain (DED) of FADD

5. Caspase 8 activated

6. Downstream activation

Question 18

What is the interection of the two pathways?

Answer 18

Caspase 8 can cleave Bid which can enter mitochondria to induce the Intrinsic (mitochondrial) pathway

Question 19

How is apoptosis regulated?

Answer 19

1. Positive Feedback and Amp Loops
2. Buffers/Dampeners
3. FLIPs
4. Decoy Receptors
5. p53

Question 20

IAPs

Answer 20

Inhibitors of Apoptosis Proteins

Bind to procaspases to prevent their activation

Bind to caspases to inhibit their activity

Inhibited by Smac/Diablo

Question 21

Smac/Diablo

Answer 21

Ibhibitor of IAPs

Question 22

FLIPs

Answer 22

Similar structure as caspase-8, but lack catalytic domain; compete for binding to FADD

Question 23

Decoy Receptors

Answer 23

Bind to apoptosis0inducing ligand, but don’t transduce signal

Question 24

p53

Answer 24

Tumor suppressor protein, mediates cell cycle/arrest/apoptosis

DNA damage activates ATM/Chk2

Initiates TX of PUMA/Noxa (pro apoptotic genes)

Question 25

What are some clinical presentations or excessive/inappropriate apoptosis?

Answer 25

Neurodegenerative Disease Immune Deficiency Disease Cardiovascular Disease Emphysema AIDS

Question 26

What are some clinical presentations of deficient apoptosis?

Answer 26

Cancer Autoimmune Disease

Question 27

What is the malfunction in apoptosis in many cancers?

Answer 27

1. IAP expression increased (inhibit apoptosis) 2. Anti-apoptotic Bcl-2 expression increased

Question 28

What are some possible strategies to reactivate apoptosis in treating cancers?

Answer 28

1. BH3 (**BID**) mimetics 2. XIAP Antagonists 3. FasL mimetics and Fas Activators

Question 29

What are the 5 main inhibitors of Apoptosis?

Answer 29

1. Bcl-2 2. Bcl-xL 3. FLIP 4. IAP 5. XIAP