Apoptosis Resistance In Cancer

Question 1

Which caspase does FADD recruit in Fas signalling

Answer 1

Caspase 8

Question 2

What happens in type 1 cells of Fas signalling

Answer 2

Caspase activation

Question 3

What happens in type 2 cells of Fas signalling

Answer 3

Cleavage of bid by caspase 8 –> leads to the intrinsic pathway of apoptosis

Question 4

Example of type I cells

Answer 4

Lympocytes

Question 5

What is the disorder that occurs due to Fas mutations

Answer 5

ALPS –> Autoimmune lymphoproliferative syndrome

Question 6

What % of colon tumours is fas altered in

Answer 6

Fas receptors are downregulated in 50% of colonic tumours

Question 7

What pathways can Fas signaling activate

Answer 7

Jak/Stat
Ras
NFkB
PI3K

Question 8

What is FLIP

Answer 8

Structurally similar to caspase 8 but no proteolytic activvity !!

Question 9

What are the 2 mechanisms of killing of cytotoxic T cells

Answer 9

1) Death receptor signalling i.e. Fas pathway

2) Granule exocytosis pathway

Question 10

What pathway leads to bad phosphorylation

Answer 10

Survival signalling i.e. Il-3 causes PI3K/Akt activation –> phosphorlates Bad

Question 11

What protein sequeusters phosphorylated bad

Answer 11

14-3-3 protein!

Question 12

Which 2 apoptosis proteins play a role in anoikis

Answer 12

Bim and Bmf

Question 13

What is anoikis

Answer 13

Anoikis is apoptosis induced by inappropriate or inadequate cell-matrix interactions

Question 14

What role does Bim have in anoikis

Answer 14

Bound to microtubules via DLC-1 and dynein motor complex

Changes in interactions releases the BH3 proteins and can cause apoptosis

Question 15

What role does Bmf have in anoikis

Answer 15

Bound to actin via DLC-2 and the myosin IV motor complex

Changes in interactions releases the BH3 proteins and can cause apoptosis

Question 16

how many forms of Bim are there

Answer 16

3

a) Bim-Xl
b) Bim-L
c) Bim-s

Question 17

Which BH3 proteins are sensitisers Only

Answer 17

Bad and Noxa

Question 18

Which BH3 proteins are direct activators

Answer 18

Bim, tBid, Puma

Question 19

What other products does the mitochondria release along with cytochrome C

Answer 19

Apoptosis Inducing Factor
Endonuclease G
Smac/Diablo
OMI

Question 20

What caspases does CIAP inhibit

Answer 20

9, 3, 7

Question 21

What pathways upregulate survivn

Answer 21

PI3K

Wnt/B-catenin

Question 22

Actions of Survivin

Answer 22

Binds and inhibits smac/diablo
Synergistic effect on XIAP
Also potent activator of NF-kB

Question 23

What structural features defines the death receptors

Answer 23

Cysteine rich extracellular domain

Have an intracellular 80 a.a. death domain

Question 24

What TRAIL Receptors are frequently decoys

Answer 24

Trail 3-5

Question 25

What drug can cause functionally active CD95L and cayse death in T cell leukaemia

Answer 25

Doxorubicin!

Question 26

What tumours often display downregulated CD95

Answer 26

Leukaemias and nueroblastomas | Often also get TRAIL silencing seen in many tumours thoguh loss of heterozygosity or epigenetic silencing

Question 27

How and which caspase is altered in neuroblastomas

Answer 27

Caspase 8 through hypermethylation of the promoter.

Question 28

What are some of the targets of NFkB Transcription

Answer 28

FLIP IAPs BCL-xl

Question 29

Name some tumours in which NFkB is constituitively active

Answer 29

Hodgkins lymphomas | Pancreatic carcinomas

Question 30

Which tumour is FLIP Shown to be high in

Answer 30

Burkitt's lymphoma

Question 31

Was CD95 agonists shown to be good

Answer 31

NO --> through to have at least some therapeutic use BUT had lethal effects as caused death in lots of hepatic cells!!!

Question 32

Why does TRAIL appear to be a promising anti-cancer target

Answer 32

No cytotoxicity | But some tumours may have resistance due to upregulation of anti-apoptotic signalling

Question 33

What can we combine TRAIL With to increase its efficact in cancer treatement

Answer 33

Combine with small moleculue inhibitor I.E. Smac-agonists --> potentiate TRAILs effects as inhibits IAPs which is overexpressed in many tumours

Question 34

How does phosphorylations of p53 affect whether apoptosis or cell sensecence occurs

Answer 34

Phoshphorylation of p53 at Ser46 leads to cytochrome C release and apoptosis

Question 35

Wht can p53 upregulate that contributes to apoptosis

Answer 35

``` p21 - a CDKI Fas ARAF-1 --> is a p53 target gene PTEN - a phosphatase PIDD - a cytoplasmic death domain that ican activate caspase 2 BAc Bid NOXA AND PUMA ```

Question 36

How does PTEN stop p53 degradation

Answer 36

Antagonist of AKT-phopshorylatio of MDMs

Question 37

Is p53 upregulating Bim shown to be key to apoptosis

Answer 37

NO mutated forms of p53 can upregulate BIM as well, hence doesnt seem to be a transcriptional dependent increae.

Question 38

Which BH3 protein is importantly linked to p53 apoptosis

Answer 38

PUMA --> p53 can upregulate Puma and has been shown to be essential for p53 apoptosis in many cell types!