Cancer genes and the cell cycle

Question 1

What is involved in the signalling pathway of any growth factor?

Answer 1

PI3-K

Question 2

What is hte function of activation of PI3-K?

Answer 2

plays an important role in cell prolfieration and idifferentation- if inhibited results in cell cyle arrest and death

Question 3

What does PIP3 generated by PI3-K recruit in cell proliferation?

Answer 3

PDK1 and Akt allowing PDK1 to phosphorylate and activate Akt

Question 4

What inhibits the conversion of PIP2 to PIP3?

Answer 4

PTEN

Question 5

What cancer are there are often PTEN mutations found in?

Answer 5

prostate; breast; lymphoid; skin; brain; thyroid; lung;kidney; liver

Question 6

What is the combined frequency of mutations in the PI3K apthway in human cancers?

Answer 6

more than 50%

Question 7

What is the effect of Akt activation?

Answer 7

inhibits forkhead box (FOX) O transcription factors FOXO1; FOXO3a and FOXO4 by phosphrylating and inactivating them

Question 8

What is a mutation in PI3-K often a sign of?

Answer 8

the first sign of tumerogenesis

Question 9

What happens to a phosphorylated FOXO factor?

Answer 9

related from the nucleus into the cytoplasm –shown by studies immunofluoresncetly tagged FOXO in cells, and adding growth factors. resulting in decreased apoptosis and regulation of cell death

Question 10

What is the effecto f FOXO3a?

Answer 10

induces p27 expression stopping hte cell cycle at G1

Question 11

What is the effect of FAOXO on apoptosis?

Answer 11

inhibits Bcl-X which binds to the micotchondial membrane preventing release of cytochrome c

Question 12

How does release of cytochrome c result in apoptosis?

Answer 12

when leaked out of mitochondria; binds to Apaf 1 in the cytoplasm which assembles into an apoptosome which recruits pro-caspase 9 and then caspase 3 which cleaves ICAD releasing CAD which cleaves DNA

Question 13

What is the function of Lapatinib?

Answer 13

dually inhibits HER2 and EGFR kinases ; specifically targets FOXO3a

Question 14

What si the function of gefitinib?

Answer 14

inhibits EGFR, specifically targets FOXO3a

Question 15

How does herceptin block the PI3-K pathway?

Answer 15

blocks HER2

Question 16

What is the expression of FOXM1 expression in cancer patients compared to normal cells?

Answer 16

much increased in cancer cells

Question 17

What inhibits FOXm1 expression?

Answer 17

FOXO1, FOXO3 and FOXO4

Question 18

What is the clinical usefuless of FOXm1 ?

Answer 18

one of the earliest genes to be activated in tumerogenesis so can be used as amarker

Question 19

What are the actions of FOXM1?

Answer 19

inhibits cellular senescence; promotes angiogeensis; cancer cell migration and invasion; clel cycle progression ; chemo drug resistance; promotes DNA damage responses

Question 20

How does FOXM1 contribute to angiogenesis?

Answer 20

increases VEGF and CXCR4

Question 21

What indicates the FOXM1 is invovled in angiogenessi and metassis?

Answer 21

100% of zebra fish injected with FOXM1 epxressing cells show angiogenesis and mets; compared with much lower angiogenesis and mets in the control– Bella; treating breast cancer cells with thiostrepton results in less migratory and invasive

Question 22

How does FOXM1 promote migration and invasion of cancer cells?

Answer 22

MMP2 and MMP9

Question 23

Why is the role of FOXM1 important in breast cancer?

Answer 23

metastasis are what kills breast cancer patietns

Question 24

What happens when FOXM1 is knocked out interms of cancer growth?

Answer 24

decreased the size and number of mammospheres

Question 25

What demonstrates the role of FOXM1 in drug resistance?

Answer 25

often overexpress FOXM1; depletion resesensitises resistant breast cancer cells to DNA damaging agents

Question 26

What is the role of FOXM1 in chemo resistance?

Answer 26

prevents the accumulation of damaged DNA and therefore damage induced prolfierative arrest

Question 27

What is p27- activated by FOXO3a invovled in?

Answer 27

senescence pathways

Question 28

What is the effect of FOXM1 deletion on cellular senesce?

Answer 28

sensitises breast cancer cell to DNA damage induced cellular senescence

Question 29

How does FOXM1 modulate the DNA damage response?

Answer 29

drives transcription of DNA damage sensors; mediators, signal transducers and effectors

Question 30

What is the mode of action of paclitaxel?

Answer 30

binds to beta-tuulin and blocks cell cycle progression through M by interrupting microtubule dynamics

Question 31

How does FOXM1 modulate paclitaxel sensitivity?

Answer 31

FOXM1 increases the expression of KIFs which play a critical role in chromosome movement and segregation during mitosis– cell can progress through M phase

Question 32

What happens when you knock out FOXM1 or KIF?

Answer 32

become sensitivei to paclitaxel

Question 33

What indicates that FOXM1 regulates KIF expression?

Answer 33

there are good correlates in cancer cells between FOXm1 and KIF

Question 34

`What is resrach in the PI3_k field looking at?

Answer 34

targeting the FOXO-FOXM1 axis by inhibiting PI3K; AKt; FOXM1

Question 35

What is hte name for a drug that inhibits FOXM1?

Answer 35

thiostrepton

Question 36

How does Akt influence apoptosis?

Answer 36

preventing FOXO entry into nucleus; inhibits MDM2 (which regultes p53); phosphorylates Bad meaning it can’t bind and inhibit the anti-apoptotic Bcl-2; activates mTOR

Question 37

How does Akt activate mTOR?

Answer 37

phosphorylates TSC1/2 which then activates Rheb allowing active Rheb to bind mTOR

Question 38

What does PTEN stand for?

Answer 38

phosphatase and tensin homolog

Question 39

How do you know that FOXM1 is important in DNA daamge responses?

Answer 39

in FOXM1 deficeint cells there are increased DNA breaks

Question 40

Why is targeting FOXM1 difficult?

Answer 40

being deficient in FOXM1 can predispose to cancer as there will be increased mutations