Block 3 Lecture 7 -- Growth Inhibition and Apoptosis

Question 1

What are signals for the intrinsic death pathway?

Answer 1

DNA damage, oxidative stress (radiation, toxin, hypoxia)

Question 2

How is the intrinsic apoptosis pathway regulated?

Answer 2

by the Bcl-2 protein family

Question 3

What are the subgroups of the Bcl-2 family?

Answer 3

1) proapoptotic (BH3-only, and non-BH3-only), 2) anti-apoptotic

Question 4

What substances escape the mitochondira upon Bax penetration?

Answer 4

1) Cyto C, 2) Procaspase 9, 3) Smac/diablo

Question 5

How does Bax insert into the mitochondrial membrane?

Answer 5

after complexing with 6-8 other Bax

Question 6

What are the components of the apoptosome?

Answer 6

oligomers of cyto c + procaspase 9 + apaf-1

Question 7

What is apaf-1?

Answer 7

co-factor for procaspase 9 activation normally found in the cytosol

Question 8

How are procaspase 9s activate?

Answer 8

NOT by simple close proximity; need Apaf-1

Question 9

What is smac/diablo?

Answer 9

mitochondrial protein that inhibits IAB

Question 10

What is IAP?

Answer 10

inhibitor of apoptosis proteins (inhibits the caspase cascade)

Question 11

How is IAP upregulated?

Answer 11

by NF-kB, an inflammatory transcription factor

Question 12

What are the steps in the intrinsic apoptosis pathway?

Answer 12

1) bid binds bax, 2) Bax inserts into membrane, 3) Cyto C + Procaspase 9 escape, 4) Apoptosome forms

Question 13

What are the extrinsic death signals?

Answer 13

TNF and FAS

Question 14

How are Procaspase 8’s activated?

Answer 14

cleave each other once in close proximity

Question 15

What is TRADD?

Answer 15

an adaptor protein that engages TNFr/FAS that has a DED to engage Procaspase 8

Question 16

What is c-flip?

Answer 16

a protein that binds the DED of TRADD to inhibit Procaspase 8 binding

Question 17

What are targets of caspases?

Answer 17

DNAse, Lamins, Actin

Question 18

What does TRAIL stand for?

Answer 18

TNF-related apoptosis-inducing ligand

Question 19

What is TRAIL?

Answer 19

member of TNF expressed in normal and cancer cells that is bound by TNF-like receptors

Question 20

Why is TRAIL important in cancer?

Answer 20

can overcome IAP-caspase sequestering, but cancer cells eventually become resistant

Question 21

What does Caspase stand for?

Answer 21

Cysteine-rich Aspartate Proteases

Question 22

What apoptosis pathway does cytotoxic chemo activate?

Answer 22

intrinsic

Question 23

How are the intrinsic/extrinsic pathways changed in cancer?

Answer 23

Bcl-2 is an oncogene; pro-apoptotic (Bax, Bid) often mutated in colorectal tumors; c-flip/IAP overexpressed

Question 24

What are potential drug targets?

Answer 24

1) c-flip and IAP; 2) rTRAIL or mAb TRAIL-r agonist; 3) Bcl-2 inhibitor (block translation or competitive); 4) upregulate Bid with HDAC inhibitors (vorinostat)

Question 25

How do the intrinsic and extrinsic pathways communicate?

Answer 25

via Bid, the common link

Question 26

What are the potential actions for Bid?

Answer 26

1) change Bax for insertion 2) be phosphorylated by ATM to yield cell cycle arrest

Question 27

What is ATM?

Answer 27

a kinase upregulated in response to DNA damage