L09: Tumour Supressor Genes Flashcards by selcan icli

What is the role of tumour suppressor genes

Stop cell growth from occuring

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

Stops

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What does the cell cycle stop at the checkpoints

To allow for DNA repair

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

Undergoes apoptosis

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What is the loss of TSG gene function due to

Genetic mutations

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If there is loos of TSG what happens

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

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

Recessive (both from mother and father)

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What is the recessive allele loss known as

Knudsons two hit hypothesis

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Where can mutation to the alleles occurs

Germ line

Somatic

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What is germ line

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

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What is somatic mutation

Mutation at the site of tumour origin

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What is the knudsons 2 hit hypothesis

2 alleles of TSG need to be eliminated

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What cancer does loss of RB1 lead to

Retinoblastoma

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What is familial retinoblastoma

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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Does familial retinoblastoma present earlier or later than somatic retinoblastoma

Earlier

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What does patients present with that have familial retinoblastoma

Bilateral disease (cancer in both eyes)

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What is somatic retinoblastoma

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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What is somatic retinoblastoma characterised by

Unilateral disease (cancer only in 1 eye)

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What is retinoblastoma

Cancer of the retina

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Does famililal retinoblastoma run in families on the pedigree

Yes

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Does somatic retinoblastoma run in the family pedigree

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What happen to the optic nerve as the tumour grows

Optic nerve thickness due to extension of tumour

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What are the presentations of retinoblastoma

White light reflection

Squint

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At what age is familial retinoblastoma diagnosed

Within 1st year

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At what age is somatic retinoblastoma diagnoses

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

What is the treatment for retinoblastoma

``` Laser therapy Chemotherapy Cryotherapy Surgery Thermotherapy Radiotherapy ```

What type of mutations occur in familial retinoblastoma on the alleles

Large deletions Single base substitution Small length mutations

What does the mutations on alleles do to the rb gene

Change its expression Change its amino acids Change its functions

What are the types of mutations that occur in somatic retinoblastoma

Gene deletions Base substantiation Small length mutations

What is type of penetrance is familial retinoblastoma associated with

Complete penetrance

What does complete penetrance mean

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

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

Familial tumours

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

Somatic mutation

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

- heterozygosity (non disjunction between sister chromatid) during mitotic recombination - hypermethylation of 5’ end of the RB1 gene

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

Recessive

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

Dominant

What is the retinoblastoma gene known as

RB1

What is the retinoblastoma gene product known as

Prb

Where does PRB function

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

What is the state of prb in the g1 phase

Hypo-phosphorylated

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

Becomes hyper phosphorlyated

What controls the phosphorylation of prb at g1 phase

Cyclin D CDK4/6

What phosphorylates prb after the restriction point

Cyclin E CDK2

What does prb function as during the cell cycle

Transcriptional repressor

Therefore what regulates the control of prb

Phosphorylation

What is the state of prb at g0 phase

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

What happens to prb at the early g1 phase

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

What happens in the late g1 phase to prb

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

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

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

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

P16ink4a

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

Binds to cyclin d cdk4/6

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

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

What is p53

A tumour suppressor gene

What is the function of p53

Protect against genetic instability in repsonse to cellular stress

What is the gene that codes for p53

Tp53

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

Mutation

Can p53 function be inhibited although tp53 gene is not mutated

Yes

What does tp53 germ line mutation give rise to

Li fraumeni syndrome

Is li fraumeni syndrome autosomal dominant or autosomal recessive

Autosomal dominant

What is p53

Sequence specific transcription factor

What can p53 activate

Apoptosis Arrest growth Induce cellular senescence Inhibit angiogenesis

When does p53 become activated

In cellular stress

What do we mean by cellular stress

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

How does the cellular stress activate p53

Signal via mediators that cause phosphorylation of P53 to become active

What can p53 work with to modulate p53 activity

Effectors

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

Transducers

At what checkpoint does p53 play a role in

G1-s checkpoint

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

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

How does p53 cause apoptosis if there is dna damage

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

When p53 has performed its function how is p53 degraded

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

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

Interaction of P53 with dna damage

What cancer does BRAC1 germ line mutation lead to

Breast cancer Ovarian cancer Prostate cancer

What is the normal role of BRCA1

DNA repair in the checkpoint via chromatin remodelling

When there is dna damage what happen to BRAC1

Phosphorylated by atm, art and chk2

What does phosphorylation of BRAC1 do

Cell cycle arrest | DNA repair

What does mutation of BRCA2 lead to

Breast carcinoma Ovarian cancer Increased risk of prostate cancer

What is the difference with BRCA1 AND 2

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

What is BRAC1 and BRAC2

A large protein

What is the role fo BRAC2

DNA Recombination repair

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

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

Overall what is the major role of BRAC2

Modulate double stranded break dna repair by interacting with RAD51

Overall what is the role of BRCA1

Cell cycle checkpoint protein for dna repair