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PHAM02 > oncogenic signlling and tumour suppressor genes > Flashcards

oncogenic signlling and tumour suppressor genes Flashcards

1
Q

% of mutations that cause cancer

A

only 5-10% of mutations cause cancer

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2
Q

What are mutations that don’t cause cancer?

A

silent mutations

they don’t change the AA sequence

they’re in non-coding regions of DNA that doesn’t affect gene function

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3
Q

difference between germline and somatic mutations

A

germline - hereditary, found in egg and sperm, can be passed down from generation and influence a person’s risk for develoing a disease

somatic - occur in non-reproductive cells, cannot be passed on, cancer cells accumulate somatic mutations, damage we do to body

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4
Q

Which more commonly cause cancer - germline or somatic mutations?

A

somatic

somatic mutations in cell signalling genes

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5
Q

gain of function mutation

A

gain of function mutation only needs one gene copy to be mutated

mutation in ONE gene causes gene to be permanently switched on

overexpression

-> most common

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6
Q

loss of function mutation

A

loss of function mutations need both gene copies to be mutated

with ONE mutation, the second gene compensates

requires both genes to be mutated for loss

-> more rare

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7
Q

What is a proto oncogene?

A

code for proteins that drive normal cell growth, healthy gene

deregulation/if it’s mutated it becomes an oncogenes

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8
Q

What is an oncogene?

A

codes for protein that causes cancer

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9
Q

functions that oncogenes can have

A
  1. point mutation: 1 AA change
    - within a control element: growth stimulating protein in excess
    - within the gene: hyperactive or degradation resistant protein (only 1 protein produced but hyperactive)
  2. gene amplification - normal protein but in excess
  3. translocation or transposition - new promoter, permanently on, normal growth stimulating protein in excess

-> gain of function mutations, accelerate growth/signalling/cell cycle in cancer

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10
Q

What are mitogens?

A

stimulatory signals that stimulate proliferation

provide the stimulatory signal to initiate transcription/translation of proteins and other molecules required for cell division

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11
Q

What is PDGF an example of?

A

mitogen

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12
Q

examples of mitogens

A

TGF-beta

PDGF

EGF

EPO

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13
Q

What does TGF-beta do?

A

inhibits proliferation

direct opposite inhibitors signal

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14
Q

What happens cells in absence of mitogen stimulation?

A

they can enter G0 phase

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15
Q

What activates tyrosine kinase receptors?

A

kinase

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16
Q

How does the MAPK signalling pathway work?

A
  • TK R dimerises
  • phosphorylation
  • RAS - Raf - MEK - ERK
  • ERK enters the nucleus
  • increased proliferation
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17
Q

What does MAPK stand for?

A

mitogen activated protein kinase

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18
Q

What does EGFR stand for?

A

epidermal growth factor receptor

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19
Q

What does EGFR do?

A

stimulates growth in epidermal and epithelial cells

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20
Q

What type of R is EGFR?

A

TK R
(activates MAPK, stimulates growth via MAPK)

and HER 1

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21
Q

What signalling does EGFR activate?

A

MAPK signalling

22
Q

3 ways EGFR can function as an oncogene

A
  1. over expression of EGFR (inc signalling)
  2. mutation in kinase domain (always active)
  3. deletion of ligand binding domain EGFR variant III (always active)
23
Q

cancers associated with EGFR overexpression/upregulation/amplification

A

adenocarcinoma of lung
rectal cancers
glioblastoma
epithelian tumours of the head and neck

24
Q

examples of EGFR receptor inhibitors

A

cetuximab

matuzumab
nimotuzumab
panitumumab

25
Q

examples of EGFR dimerisation inhibitors (HER2 inhibitors)

A

trastuzumab

pertuzumab

26
Q

examples of TKIs

A

gefitinib
erlotinib
lapatinib

27
Q

How many parts of the EGFR can be targeted/blocked and where?

A

3

EGFR R inhibitors (outside)
EGFR dimerisation inhibitors (outside)
TKIs (inside)

28
Q

What are tumour suppressor genes?

A

genes that protect cells following damage

suppress cellular proliferation

initiate apoptosis

in response to checkpoints or growth suppression signals

29
Q

homozygous, heterozygous and loss of heterozygosity in tumour suppressor genes

A

homozygous - both genes are WT, protein is active, normal

heterozygous - one mutated gene but the other is WT, protein is active, increased risk

loss of heterozygosity (LOH) - 2nd gene is now mutated, protein lost/inactive, cancer likely
-> loss of function

30
Q

2 hit hypotnesis loss of function theory

A

Rb1 gene is a tumour suppressor gene

loss of function leads to childhood retinal cancer - retinoblastoma

sporatic mutation (somatic) of 2 chromosomes at the same site is very unlikely

Tx/removal of eye leads to no further cancer in sporadic mutations

inherited Rb mutation leads to x500 increased risk of retinoblastoma occurrence

31
Q

guardian of the genome

A

p53

32
Q

% of cancers that p53 is mutated in

A

50%

33
Q

What mutation is most common in p53 in cancers?

A

missense mutation in one allele

results in high levels of non-functional protein

34
Q

most commonly mutated tumour suppressor gene in cancer

A

p53

35
Q

p53 and the 2 hit hypothesis

A

it doesn’t follow the 2 hit rule

mutant p53 outcompetes the normal variant

loss of one p53 gene is tolerated

one gene mutated, pp53 function NOT normal

loss of function with one mutation

36
Q

Is p53 an oncogene?

A

NO

37
Q

How does p53 work?

A

TSG

DNA damage activates p53

p53 activates p21

p21 inhibits cell cycle, reduces proliferation

p53 controlled by MDM2

inhibiting MDM2 enables p53 to function in cancer

38
Q

What controls p53?

A

MDM2

39
Q

example of gene alteration that is inherited in colon cancer

A

APC gene - familial adenomatous polposis

40
Q

apoptosis

A

programmed cell death

cells shrink, condense and fragment

no inflammatory response and undergo phagocytosis

41
Q

difference between apoptosis and necrosis

A

necrosis - sudden death, swell and burst which causes inflammatory response

apoptosis - programmed, not sudden, shrink and condense, no inflammatory response, phagocytosis

42
Q

enzymes that control apoptosis

A

proteases (end in -ase)

CASPASES

43
Q

What do caspase contain?

A

contain cysteine active sites

44
Q

Where do caspases cleave targets at?

A

aspartic acid

cASPases

45
Q

2 types of caspases

A
  1. initiator caspases
  2. executioner caspases
46
Q

examples of initiator caspases

A

caspases 8 and 9

47
Q

examples of executioner caspases

A

caspases 3, 6 and 7

48
Q

How do caspases work?

A

signals trigger initiarot caspases

initiators dimerise and activate

executioner caspases degrate nuclear proteins

caspase activated DNAse (CAD) is activated which cute up DNA in the cell

degrades cell adhesion molecules

49
Q

CAD

A

caspase activated DNAse

cuts up DNA in the cell

50
Q

Can apoptosis be stopped?

A

NO

once apoptosis starts, it can’t be reversed

PHAM02 (32 decks)

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