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CAN > L09: Tumour Supressor Genes > Flashcards

L09: Tumour Supressor Genes Flashcards

1
Q

What is the role of tumour suppressor genes

A

Stop cell growth from occuring

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2
Q

For example if there is damage to the dna due to ionizing radiation what happen to the cell cycle

A

Stops

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3
Q

What does the cell cycle stop at the checkpoints

A

To allow for DNA repair

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4
Q

If the damage on DNA is too great what happens to the cell

A

Undergoes apoptosis

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5
Q

What is the loss of TSG gene function due to

A

Genetic mutations

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6
Q

If there is loos of TSG what happens

A

Loss of growth suppression
Loss of cell cycle checkpoint control
Increased cell proliferation

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7
Q

How many alleles need to be mutated to lose the function of TSG

A

Recessive (both from mother and father)

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8
Q

What is the recessive allele loss known as

A

Knudsons two hit hypothesis

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9
Q

Where can mutation to the alleles occurs

A

Germ line

Somatic

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10
Q

What is germ line

A

If cancer is heritable then mutation occurs in the sex cells i.e germ line

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11
Q

What is somatic mutation

A

Mutation at the site of tumour origin

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12
Q

What is the knudsons 2 hit hypothesis

A

2 alleles of TSG need to be eliminated

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13
Q

What cancer does loss of RB1 lead to

A

Retinoblastoma

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14
Q

What is familial retinoblastoma

A

1) fertilised egg has one mutant allele of rb and one normal rb allele
2) somatic mutation than occurs where the cell will originate resulting in 2 rb mutating allele

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15
Q

Does familial retinoblastoma present earlier or later than somatic retinoblastoma

A

Earlier

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16
Q

What does patients present with that have familial retinoblastoma

A

Bilateral disease (cancer in both eyes)

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17
Q

What is somatic retinoblastoma

A

1) fertilised egg has a both normal rb alleles
2) first somatic mutation occurs resulting in 1 rb mutated allele and 1 normal allele
3) second mutation occurs resulting in 2 rb mutated alleles

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18
Q

What is somatic retinoblastoma characterised by

A

Unilateral disease (cancer only in 1 eye)

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19
Q

What is retinoblastoma

A

Cancer of the retina

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20
Q

Does famililal retinoblastoma run in families on the pedigree

A

Yes

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21
Q

Does somatic retinoblastoma run in the family pedigree

A

No

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22
Q

What happen to the optic nerve as the tumour grows

A

Optic nerve thickness due to extension of tumour

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23
Q

What are the presentations of retinoblastoma

A

White light reflection

Squint

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24
Q

At what age is familial retinoblastoma diagnosed

A

Within 1st year

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25
Q

At what age is somatic retinoblastoma diagnoses

A

Between 24 months and 30 months (2 year and 2.5)

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26
Q

What is the treatment for retinoblastoma

A 
Laser therapy
Chemotherapy 
Cryotherapy 
Surgery 
Thermotherapy 
Radiotherapy
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27
Q

What type of mutations occur in familial retinoblastoma on the alleles

A

Large deletions
Single base substitution
Small length mutations

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28
Q

What does the mutations on alleles do to the rb gene

A

Change its expression
Change its amino acids
Change its functions

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29
Q

What are the types of mutations that occur in somatic retinoblastoma

A

Gene deletions
Base substantiation
Small length mutations

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30
Q

What is type of penetrance is familial retinoblastoma associated with

A

Complete penetrance

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31
Q

What does complete penetrance mean

A

Although one mutant ant allele is inherited and the gene level is receives, it is very likely the disease will occur

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32
Q

Does somatic and familial retinoblastoma have increases risk of developing multiple tumours

A

Familial tumours

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33
Q

In both familial and somatic retinoblastoma what is the 2nd mutation that has to occur to cause disease

A

Somatic mutation

34
Q

What is the 2nd mutation in both familial and somatic retinoblastoma due to

A
  • heterozygosity (non disjunction between sister chromatid) during mitotic recombination
  • hypermethylation of 5’ end of the RB1 gene
35
Q

What does TSG have to be like at the genetic level to become inactivated

A

Recessive

36
Q

At the cellular level what does TSGs have to be like at the cellular level

A

Dominant

37
Q

What is the retinoblastoma gene known as

A

RB1

38
Q

What is the retinoblastoma gene product known as

A

Prb

39
Q

Where does PRB function

A

In the cell cycle at the restriction point of between early g1 and late g1 phase before passing into the s phase

40
Q

What is the state of prb in the g1 phase

A

Hypo-phosphorylated

41
Q

When the cell passes the restriction point what happens to the state of prb

A

Becomes hyper phosphorlyated

42
Q

What controls the phosphorylation of prb at g1 phase

A

Cyclin D CDK4/6

43
Q

What phosphorylates prb after the restriction point

A

Cyclin E CDK2

44
Q

What does prb function as during the cell cycle

A

Transcriptional repressor

45
Q

Therefore what regulates the control of prb

A

Phosphorylation

46
Q

What is the state of prb at g0 phase

A

1) prb is bound to E2F and DP regulator promotes to inhibit it
2) cell cycle progression if prevented and transcription of genes for cell cycle progression

47
Q

What happens to prb at the early g1 phase

A

1) prb is hypo-phosphorylated via cyclin D CDK4/6
2) this changes structure of in prb
3) HDAC detaches from prb
4) p300 primes E2F responsive promotes
5) transcription activation occurs

48
Q

What happens in the late g1 phase to prb

A

1) becomes hyper-phosphorylated by cyclin E cdk2 complex
2) prb detaches from the E2F and DP complex
3) E2F/DP drives transcription of genes needed top pass through restriction point

49
Q

In cancer when prb is inactivated what happens to the restriction point

A

Bypassed as E2F + DP complex are active for uncontrolled entry to s phase

50
Q

In a normal cell when there is cellular stress detected what can stop the phosphorylation of prb by cyclin d cdk4/6

A

P16ink4a

51
Q

What does p16ink4a do to the cyclin d cdk4/6 to stop it from phosphorlayting prb and promote growth arrest

A

Binds to cyclin d cdk4/6

52
Q

In cancer what can happen to p16ink4a to stop the growth arrest

A

Mutated to cyclin d cdk4/2 continues to phosphorylate PRB and continue the cell cycle

53
Q

What is p53

A

A tumour suppressor gene

54
Q

What is the function of p53

A

Protect against genetic instability in repsonse to cellular stress

55
Q

What is the gene that codes for p53

A

Tp53

56
Q

What can happen to the tp53 gene in cancer to cause mutation of p53

A

Mutation

57
Q

Can p53 function be inhibited although tp53 gene is not mutated

A

Yes

58
Q

What does tp53 germ line mutation give rise to

A

Li fraumeni syndrome

59
Q

Is li fraumeni syndrome autosomal dominant or autosomal recessive

A

Autosomal dominant

60
Q

What is p53

A

Sequence specific transcription factor

61
Q

What can p53 activate

A

Apoptosis
Arrest growth
Induce cellular senescence
Inhibit angiogenesis

62
Q

When does p53 become activated

A

In cellular stress

63
Q

What do we mean by cellular stress

A 
DNA damage 
Hypoxia 
Reactive oxygen species 
Oncogene activation 
Loss of adhesion 
Changes in translation of protein via ribosome
64
Q

How does the cellular stress activate p53

A

Signal via mediators that cause phosphorylation of P53 to become active

65
Q

What can p53 work with to modulate p53 activity

A

Effectors

66
Q

When p53 is active what does it interact with to give its specific effect

A

Transducers

67
Q

At what checkpoint does p53 play a role in

A

G1-s checkpoint

68
Q

When there is dna damage at the g-s checkpoint describe what happens

A

1) dna damage is sensed by proteins which recruit atm
2) ATM undergoes auto phosphorylation
3) ATM directly phosphorylase P53
4) or ATM phosphorylates CHK2 which activates p53
5) or p53ARF inhibits MDM2 so it cannot inhibit p53
6) active p53 drives expression of p21
7) p21 inhibits CDK4/6 AND CDK2 which prevents the progression of the cell from the g1 to s phase
8) if dna damage is too greate p53 induces PUMA and NOXA that inhibit BCL-2 (anti-apoptosis molecule) so apoptosis can occur

69
Q

How does p53 cause apoptosis if there is dna damage

A

Active p53causes espresso of pro-apoptic molecules which active apoptosis
Or
Induce PUMA and NOXA that inhibit BCL-2 (anti apoptosis molecule)

70
Q

When p53 has performed its function how is p53 degraded

A

1) p53 causes the expression of MDM2
2) MDM2 promotes p53 poly-ubiquitylation
3) 26s proteasome recognises the p3 and degrades it

71
Q

In cancer when p53 is mutated what does it most likely affect

A

Interaction of P53 with dna damage

72
Q

What cancer does BRAC1 germ line mutation lead to

A

Breast cancer
Ovarian cancer
Prostate cancer

73
Q

What is the normal role of BRCA1

A

DNA repair in the checkpoint via chromatin remodelling

74
Q

When there is dna damage what happen to BRAC1

A

Phosphorylated by atm, art and chk2

75
Q

What does phosphorylation of BRAC1 do

A

Cell cycle arrest

DNA repair

76
Q

What does mutation of BRCA2 lead to

A

Breast carcinoma
Ovarian cancer
Increased risk of prostate cancer

77
Q

What is the difference with BRCA1 AND 2

A

They are both mutations that lead to breast cancer but are present with different tumour histology

78
Q

What is BRAC1 and BRAC2

A

A large protein

79
Q

What is the role fo BRAC2

A

DNA Recombination repair

80
Q

Describe the role of BRCA2 when the double stranded dna is reseceted into single stand dna

A

1) SSDNA becomes coated with RPA complex
2) BRCA2 associated with RAD51 to displace the RPA complex from the single stranded DNA
3) this forms RAD51 nucleoprotein filament
4) dna is repaired

81
Q

Overall what is the major role of BRAC2

A

Modulate double stranded break dna repair by interacting with RAD51

82
Q

Overall what is the role of BRCA1

A

Cell cycle checkpoint protein for dna repair

CAN (25 decks)

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