TSG Flashcards

1
Q

What are the main suppressor genes that play a role in cell growth and death?

A

p53 and pRB

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2
Q

What happens to a TSG in cancer?

A

The TSG is inactive allowing uncontrolled proliferation and avoidance of death due to loss of suppression and checkpoints.

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3
Q

If a cancer results from an inherited gene, where in the body will the cancer be present?

A

In every cell but this is not common as most mutations are somatic

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4
Q

What type of cancer is associated with the loss of RB1?

A

Retinoblastoma and osteosarcoma

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5
Q

What type of cancer is associated with the loss of p53?

A

Li-Fraumeni:

Breast, adrenal and most other sarcomas

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6
Q

Where does the cancer develop with the loss of ATM?

A

T and B cells

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7
Q

Which type of cancer is associated with the loss of BRCA1/2?

A

Breast, ovarian and prostate

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8
Q

What is a TSG?

A

Produce proteins to negatively regulate growth and form components of cell cycle checkpoints to ensure genome integrity when under stress.

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9
Q

How many alleles must be lost for a TSG to be inactive?

A

Both alleles as TSG are recessive in cancer = Knudson’s two hit hypothesis

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10
Q

How are both alleles lost in an inherited manner? How are both alleles lost in a non inherited manner?

A

Inherited: 1st mutation is germ line + 2nd mutation is somatic = bilateral
Non: Both mutations are somatic and arise in the same cell where the cancer originates = unilateral

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11
Q

What is retinoblastoma?

A

A cancer of the retina arising due to a mutation in Rb gene. Metastases can develop out of the eye, displace the retina and compress the optic nerve

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12
Q

How does a child present with retinoblastoma?

A

White light reflection as it reflects off the tumour mass.

Squint

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13
Q

When does a child present with retinoblastoma?

A

If Bilateral it presents within the first year

If Unilateral it presents later, around 24-30mnths as 2 somatic hits are needed.

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14
Q

What are the characteristics of a retinoblastoma that results from an inhertited mutation?

A

Multiple bilateral tumours with early onset and the gene progresses through generations. Increases the risk of other cancers over time

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15
Q

What are the characteristics of a retinoblastoma that results from a somatic mutation?

A

Single, unilateral tumour with late onset.

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16
Q

How can retinoblastoma be treated?

A

Laser, thermo/chemo/radiotherapy or surgery

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17
Q

What is the familial mutation that contributes to the retinoblastoma?

A

Large deletion or single base substitution or small length mutations that cause a loss in reading frame.
Most are autosomal dominant = complete penetrance (presents in all with the mutation)
Rare alleles will show incomplete penetrance

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18
Q

What is the cause for the somatic mutation that contributes to retinoblastoma?

A

Gene deletions, base substitutions, small length mutations.

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19
Q

What happens to the allele at a locus when both are mutated?

A

Lose heterozygosity of the RB locus as become mutant

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20
Q

What is the function of RB?

A

Creates a restriction point at G1/S, acting as a transcriptional repressor.

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21
Q

What is G1 phase driven by and what happens in this stage?

A

Cyclin/Cdk activity drives DNA replication in G1. Once it has passed the G1/s checkpoint the cell is committed to the cell cycle an cannot be moved to G0.

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22
Q

How does pRB repress transcription? What other proteins are involved?

A

pRB is associated with a complex formed by E2F family of TF, p300 and HDAC to repress transcription

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23
Q

What is p300?

A

A histone acetylase to prime transcription

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24
Q

What is HDAC?

A

A histone deacetylase that represses transcription.

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25
Q

What causes pRb to be phosphorylated and what does this result in?

A

Cyclin D/ccdk4 phosphorylates to activate pRB. It causes dissociation of HDAC from the complex. Whilst pRB is still associated with E2F, only some transcription can occur as E2F is not fully active.

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26
Q

How does E2F become fully activated?

A

In the late stage of G1, Cyclin E/cdk2 phosphorylated RB fully so that it dissociates from E2F complex to drive transcription of the genes needed for cell cycle progression into S phase.

27
Q

How is pRB regulated?

A

By p16 Cdk4 inhibitor. In response to stress, p16 levels rise and bind to cdk to prevent phosphorylation of pRB so it remains bound to inhibit E2F. It results in cellular senescence.

28
Q

What is p16?

A

A TSG

29
Q

How is p16 lost in cancer? What is the consequence of this?

A

Mutation or epigenetic silencing. This means E2F is constitutively active and cell cycle progresses.

30
Q

What is p53?

A

A TSG that is a sequence specific TF for proapoptotic activity, growth arrest, induction of cellular senescence and inhibits angiogenesis.

31
Q

What is the most common type of mutation to results in p53?

A

Missense mutation - a change in AA altering its function and inhibiting the p53 pathway

32
Q

Why is p53 inactive in nearly all cancers?

A

Either due to direct mutation or due to upstream and downstream proteins preventing it from functioning.

33
Q

What is Li-Fraumeni?

A

Results from p53 mutations. A heterogeneous inherited syndrome of autosomal dominant nature. Causes multiple early onset tumours mostly in soft tissues, bone, breast, brain, adrenal, leukaemia.

34
Q

What does the loss of p53 at later stages of cancer result in?

A

Increased severity

35
Q

What does a mutation in p53 result in?

A

Promotes genetic instability and oncogenic potential. Loses ability to activate the transcription of its gene to protein and therefor loses its growth suppressive properties.

36
Q

Why can p53 have multiple isoforms?

A

393 AA protein that can form 13 isoforms through slicing. All can exist in one cell together.

37
Q

What domains are present in the p53 TF?

A

N terminal transactivation = activates transcription
Proline-rich domaine = stimulates apoptosis
Sequence specific DNA binding = Binds to promoters of p53 response genes to drive transcription
Oligomerisation = allows p53 to function as a tetramer
C terminal regulatory domain

38
Q

How does p53 produce its actions?

A

p53 binds to response elements as a tetramer to drive transcription of genes when associated with acetylases.

39
Q

How is p53 regulated?

A

It responds to signals so is controlled by the interaction with other proteins such as acetylases
or post translationally modified via acetylation by p300
or phosphorylation.
The signals determine which response elements it binds to

40
Q

Which domains are affected most by regulation?

A

Transactivation and regulatory domain at terminal regions

41
Q

What does p53 respond to?

A

Cellular stress. Normally inactive in nonstressed cells. Response the the type and extent of stress

  • DNA damage
  • ROS
  • Ribosomal
  • Oncogene activation
  • Hypoxia
  • Loss of adhesion
42
Q

How is p53 activated?

A

Upon cellular stress ATM is activated. ATM has protein kinase activity to autophsophorylate and activate itself for:

  • to phosphorylate the N terminal of p53 to regulate its activity directly
  • Phosphorylate Chk2 to phosphorylate p53
  • activate p19
43
Q

What is mdm2?

A

A protein ubiquitin ligase that tags proteins onto substrates to target it for degradation by proteosome. It -vely regulates p53.

44
Q

What is the function of p19?

A

p19 inhibits mdm2 to activate p53

45
Q

What determines the p53 response?

A

The type of stress will determine which genes p53 regulates the transcription of.

46
Q

What responses can p53 bring about?

A

Antiangiogensis
Growth arrest
DNA repair
Apoptosis

47
Q

Which checkpoint does p53 play a role in?

A

G1/S

48
Q

How does p53 prevent cell cycle progression?

A

When active it drives transcription of p21 cdk inhibitor that binds with Cyclin/cdk complexes to inhibit the cell cylce and prevent progression into S phase. The cell can then repair its DNA to reenter the cycle.

49
Q

How does p53 induce apoptosis?

A

Through transcriptional mechanisms producing proapoptotic molecules such as BAX, PUMA
Through nontranscriptional mechanisms via regulation of BCL-2 family proteins

50
Q

What it the autoregulatory feedback loop of p53?

A

p53 drives its own destruction by being in a loop with mdm2. Active p53 indicues mdm2 expression and then mdm2 drives ubiquitylation of p53 protein so that it is targeted by 26S proteosome for degradation.

51
Q

What is the most common p53 mutation?

A

Missense substitution of argenine that changes the charge interactions for DNA. It prevents p53 from interacting with DNA

52
Q

What is BRCA 1?

A

A protein that is an E3 ubiquitin ligase to promote ubiquitylation. It functions during DNA damage by activating checkpoints or DNA repair. Involved in chromatin remodelling.

53
Q

How many mutations can occur in the BRCA 1 coding region and give an example.

A

> 300.

18JclelAG found within the Ashkenazic Jewish population

54
Q

What is the risk with BRCA 1?

A

Predisposes to early onset breast carcinoma and ovarian tumours, with some association to prostate.

55
Q

How is BRCA 1 involved in transcription?

A

By binding to cmyc oncogene or p53 TFs

56
Q

What happens on activation of BRCA 1?

A

Activated by phosphorylation to regulate cell cycle arrest for DS breaks. In response to ionising radiation, ATM phosphorylates BRCA to promote arrest in S phase or in G2/M and it influences p53 at G1/S.

57
Q

What are the two main functions of BRCA 1?

A

Cell cycle checkpoint control

Promotes homologous recombination repair via CHK2

58
Q

What cancers does BRCA 2 predispose to?

A

Early onset breast carcinoma and ovarian tumours.

Increases risk of prostate, gall bladder, bile duct, stomach and malignant melanoma

59
Q

What type of anaemia is BRCA 2 associated with?

A

Fanconi Anaemia

60
Q

Are BRCA mutations germline or somatic?

A

Germline.

If somatic occur they do not contribute to the feature of sporadic cancer and early onset.

61
Q

How are BRCA 1 and 2 tumours histologically different?

A

BRCA 1 tumours have higher mitotic rate and more lymphocyte infiltration.
BRCA 2 have more tubule formation

62
Q

What is the function of BRCA 2?

A

DS break recombination repair through Rad51

63
Q

What is the difference in the functions of BRCA1 and 2?

A

Both are involved in DNA damage response from ionising radiation:
DS break recombination repair. BRCA 1 through CHK2 and BRCA 2 through Rad51
BRCA 1 plays a wider role in cell cycle checkpoints.

64
Q

What does the loss of either gene result in?

A

Increased sensitivity of cells to ionising radiation