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Module 3 > Cancer genes and the cell cycle > Flashcards

Cancer genes and the cell cycle Flashcards

1
Q

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

A

PI3-K

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2
Q

What is hte function of activation of PI3-K?

A

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

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3
Q

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

A

PDK1 and Akt allowing PDK1 to phosphorylate and activate Akt

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4
Q

What inhibits the conversion of PIP2 to PIP3?

A

PTEN

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5
Q

What cancer are there are often PTEN mutations found in?

A

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

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6
Q

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

A

more than 50%

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7
Q

What is the effect of Akt activation?

A

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

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8
Q

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

A

the first sign of tumerogenesis

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9
Q

What happens to a phosphorylated FOXO factor?

A

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

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10
Q

What is the effecto f FOXO3a?

A

induces p27 expression stopping hte cell cycle at G1

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11
Q

What is the effect of FAOXO on apoptosis?

A

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

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12
Q

How does release of cytochrome c result in apoptosis?

A

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

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13
Q

What is the function of Lapatinib?

A

dually inhibits HER2 and EGFR kinases ; specifically targets FOXO3a

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14
Q

What si the function of gefitinib?

A

inhibits EGFR, specifically targets FOXO3a

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15
Q

How does herceptin block the PI3-K pathway?

A

blocks HER2

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16
Q

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

A

much increased in cancer cells

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17
Q

What inhibits FOXm1 expression?

A

FOXO1, FOXO3 and FOXO4

18
Q

What is the clinical usefuless of FOXm1 ?

A

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

19
Q

What are the actions of FOXM1?

A

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

20
Q

How does FOXM1 contribute to angiogenesis?

A

increases VEGF and CXCR4

21
Q

What indicates the FOXM1 is invovled in angiogenessi and metassis?

A

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

22
Q

How does FOXM1 promote migration and invasion of cancer cells?

A

MMP2 and MMP9

23
Q

Why is the role of FOXM1 important in breast cancer?

A

metastasis are what kills breast cancer patietns

24
Q

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

A

decreased the size and number of mammospheres

25
Q

What demonstrates the role of FOXM1 in drug resistance?

A

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

26
Q

What is the role of FOXM1 in chemo resistance?

A

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

27
Q

What is p27- activated by FOXO3a invovled in?

A

senescence pathways

28
Q

What is the effect of FOXM1 deletion on cellular senesce?

A

sensitises breast cancer cell to DNA damage induced cellular senescence

29
Q

How does FOXM1 modulate the DNA damage response?

A

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

30
Q

What is the mode of action of paclitaxel?

A

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

31
Q

How does FOXM1 modulate paclitaxel sensitivity?

A

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

32
Q

What happens when you knock out FOXM1 or KIF?

A

become sensitivei to paclitaxel

33
Q

What indicates that FOXM1 regulates KIF expression?

A

there are good correlates in cancer cells between FOXm1 and KIF

34
Q

`What is resrach in the PI3_k field looking at?

A

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

35
Q

What is hte name for a drug that inhibits FOXM1?

A

thiostrepton

36
Q

How does Akt influence apoptosis?

A

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

37
Q

How does Akt activate mTOR?

A

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

38
Q

What does PTEN stand for?

A

phosphatase and tensin homolog

39
Q

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

A

in FOXM1 deficeint cells there are increased DNA breaks

40
Q

Why is targeting FOXM1 difficult?

A

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

Module 3 (33 decks)

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