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Pharm Decks > Lecture 3 - Tumour Suppressor Genes > Flashcards

Lecture 3 - Tumour Suppressor Genes Flashcards

1
Q

What is a tumour suppressor gene?

A

Genes which normally function to restrict growth
Induce cell cycle arrest to induce apoptosis of damaged cells

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2
Q

Main allelic difference between oncogenes and tumour suppressor genes

A
  • oncogenes are dominant so only need mutation in one allele for a constitutively active protein
  • tumour suppressor genes are recessive so need mutations/loss of copies in both alleles for cancer to occur
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3
Q

What kind of mutations are common in patients carrying tumour suppressor gene mutations?

A

Germline/inherited mutations
Therefore only one sporadic mutation required in lifetime to have 2 recessive mutations

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4
Q

What kind of mutations usually occur in tumour suppressor genes and how do these lead to nonfunctional proteins?

A
  • Point mutations or deletions which result in no protein or a protein with altered functions
    e.g. early stop codons causing non-functional truncated proteins
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5
Q

What are the 6 main classes of tumour suppressor genes?

A
  1. Growth/development suppressors
  2. Cell cycle checkpoint proteins
  3. Cell cycle inhibitors
  4. Inducers of apoptosis
  5. DNA repair enzymes
  6. Developmental pathways
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6
Q

Example of a tumour suppressor gene in the growth/development suppressors class

A

TGF Beta acts as a break on cell signalling through the recruitment of SMAD proteins

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7
Q

A mutation of what gene can be inherited leading to increased risk of colon cancer?

A

APC gene

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8
Q

What occurs in APC to make you more susceptible to colon cancer?

A
  • Loss of function of APC gene which can accelerate process of formation of precancerous intestinal polyps
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9
Q

What hereditary predisposition is often associated with breast cancer and inherited?

A

BRCA1

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10
Q

What is the normal function of BRCA1/2?

A

DNA repair enzymes
Involved in homologous recombination and double strand break repair

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11
Q

What can a mutation in BRCA cause?

A

mutations lead to defective recombination which destabilises the genome
May cause chromosomal rearrangements

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12
Q

If BRCA is in every cell type, why do we usually see it associated with breast and ovarian cancer?

A
  • May be because reactive oxygen species (ROS) which are produced in the menstrual cycle cause DNA damage and are therefore dependent on the BRCA to repair the damage each month
  • Loss of the enzymes can lead to accumulation of mutation
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13
Q

What inhibitor can be used to target BRCA deficient cells?

A

Poly ADP Ribose Polymerase inhibitors (PARP)

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14
Q

What would happen if you block PARP pathway in normal cells?

A

Normal cells have a BRCA mediated repair pathway, therefore blocking PARP will mean they can still repair their DNA and survive

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15
Q

What would happen if you blocked PARP pathway in BRCA deficient tumour cells?

A

Block PARP and also have deficient BRCA so the tumour cells can’t repair through the PARP or BRCA pathway
Tumour gets more and more mutations and damaged and dies

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16
Q

What is the name for the area of treatment using PARP inhibitors in BRCA deficient tumours?

A

Selective lethality

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17
Q

What happens to tumour suppressor genes to cause the cancer?

A

Loss of function

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18
Q

What was the first tumour suppressor gene to be identfied?

A

Retinoblastoma

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19
Q

What causes loss of function of Retinoblastoma and what does this lead to?

A

Point mutation or truncation
- Leads to development of tumours in the retina

20
Q

What is pRb and what is its normal function in the cell?

A
  • Retinoblastoma protein
  • Normally it binds and sequesters E2F transcription factors, acting as a break on the cell cycle
21
Q

What does loss of function in pRb mean for the function of the protein in the cell and the cell fate?

A

There is no functional protein, so cell cycle can continue without extra checks

22
Q

Virus example and how it is involved with pRb

A

The E7 subunit of HPV can bind and inhibit pRb

23
Q

What happens if there is no functional pRb in the context of the cell cycle?

A

E2F is free and active all the time to drive the cell into S phase

24
Q

What is P53 and what kind of molecule is it in its functional state?

A

A transcriptional regulator, the guardian of the genome
Tetrameric (4 molecule come together)

25
Q

How does P53 work as a tumour suppressor?

A

Prevents tumour development by checking integrity of the DNA.
If DNA damaged can upregulate repair mechanisms
Upregulates apoptotic enzymes or repair enzymes

26
Q

In resting cells what is the role of P53

A

Upregulates antioxidant genes to counteract any ROS

27
Q

P53 state in normal cells

A

Present at low levels bound to MDM2

28
Q

What do stress signals cause to happen to P53?

A

Signals inhibit MDM2 which frees up P53 to act as a transcription factor, binding to damaged DNA and upregulating DNA repair enzymes

29
Q

Example of stress factors which will trigger activation and upregulation of P53

A

DNA damage
Oncogenes
Hypoxia
Loss of trophins

30
Q

Examples of responses of P53 in response to stress

A

Cell cycle arrest
Differentiation
DNA repair
Apoptosis
Senescence

31
Q

How does P53 trigger apoptosis

A

Upregulating apoptotic proteins Bad and Bax

32
Q

Examples of P53 mutations which cause LUNG cancer

A

Benzo(a) pyrine in cigarettes generates mutagens
Causes G>T transversions in DNA

33
Q

Examples of P53 mutations in LIVER cancer

A

Aflatoxin leads to G>T transversion in P53

34
Q

Brief structure of P53

A
  • N terminal domain contains MDM2 binding site
  • Middle section DNA binding domain
  • C terminal contains tetramerization domain where 4 P53 molecules bind to each other
35
Q

How does the HPV effect P53?

A

E6 subunit of HPV binds to P53, preventing it from binding to the DNA

36
Q

What is different about P53 as a tumour suppressor compared to others?

A

Only need one mutated copy of the P53 gene to predispose the cancer
Doesn’t follow the recessive rule

37
Q

Why does the recessive rule not follow for P53?

A
  • due to the tetrameric nature of P53, if one protein has a mutation the 4 molecule complex cannot form
  • the mutated protein is more stable than the wild type protein so it hangs around for longer and chance of being in the tetramer is higher
38
Q

What is the issue with using chemotherapy agents to treat cancers with P53 mutations?

A
  • Chemotherapy induces DNA damage in cancer cells so they die
  • relys on the apoptopic pathway to therefore kill off the damaged cells
  • need P53 to do this
  • therefore all WT cells die and P53 mutant cells survive
39
Q

P53 status in cervical cancer and how this contributes to cervical cancer

A

Rarely mutated, it is instead bound by the HPV E6 which mediates the degradation of the P53 so it cannot carry out function

40
Q

What can mean you cannot fight HPV off and are more susceptible to cervical cancer?

A

P53 polymorphisms

41
Q

Examples of alternative therapeutic approaches to P53?

A

Advexin - adenoviral delivery of WT P53 to outcompete the mutated P53 proteins

CDB3/ PRIMA-1 stabilises mutant p53 and restores transcriptional function

Nutlin - MDM2 inhibitors

Pifithrin –suppresses endogenous p53 in normal tissue to reduce susceptibility to chemotherapy/ radiation induced apoptosis

42
Q

Outline how Onyx 015 works as a synthetic lethality approach to treat mutated P53 cancers

A
  • Can replicate in cells by inactivating p53 (E1B) and pRb (E1A) to drive the cell cycle and drive viral load
  • The Onyx version is deficient in the protein which inactivates P53
  • In WT cells with P53 the virus activates the P53 pathway causing cell cycle arrest and blocking viral replication
  • In cancer cells with no functional P53, there is nothing to cause cell cycle arrest so the virus replicates and the E1A inactivates pRb which drives cell through cell cycle and virus causes cell lysis of the cancer cell
43
Q

Does LOF make cancer cells more resistant or more reactive to cancer therapies?

A

More resistant

44
Q

What is a hereditary predisposition?

A

Inheriting a germline mutation in one allele

45
Q

What are common examples of hereditary predispositions?

A

APC - precancerous intestinal polyps, increased risk of colon cancer

BRCA1- 60% probability of inheriting breast/ovarian cancer

Possibly lung also

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