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Stem Cell and Cancer > L13 - Tumour Suppressor Genes > Flashcards

L13 - Tumour Suppressor Genes Flashcards

1
Q

When and how were tumour suppressor genes identified?

A

1970s-1980s - experimental evidence of a second growth controlling gene - suppress cell proliferation
Tumour suppressor genes involved in cancer when inactivated or lost

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2
Q

Do viral oncogenes have a dominant or recessive effect?

A

Dominant

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3
Q

Infection of a normal cells results in?

A

Cell transformation to a cancer cell
Happens despite continued expression of opposite cellular genes that usually mediate normal cell proliferation
Cancerous cell growth - dominant phenotype
Normal cell growth – recessive phenotype

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4
Q

How was it discovered that non-viral oncogenes have a dominant effect?

A

Cell fusion technique –> comparison of 2 alternative alleles and specified phenotypes when both alleles forced to coexist
- Dominant allele wins

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5
Q

How are two different phenotypes grown together?

A

Fusing agent is Sendai virus or PEG

The hybrid cell formed is a heterokaryon

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6
Q

What are the two possible outcomes when a cancer cell is fused with a normal cell?

A

Hybrid cell
Not tumorigenic
- Cancer alleles are recessive - correct pathway
Tumorigenic
- Cancer alleles are dominant
Normal cells carry tumour suppresser genes that constrain their proliferation - inactivated during tumour development

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7
Q

What were the arguments for and against tumour suppressor genes?

A

For
- Easier to lose a TSG by mutation than activating an oncogene
Against
- 2 copies of TSG must be lost –> 2 genetic alterations complex and unlikely in short period of time
Can’t be addressed with fusion experiment - looked at retinoblastoma

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8
Q

What was looked at to understand the genetic reasons for the recessive phenotype of cancer cells?

A

Retinoblastoma
Tumour of the retina, arising in photoreceptor precursors
1:20,000 children
Diagnosed from birth up to the age of 6 to 8 years

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9
Q

What are the two forms of retinoblastoma?

A

Sporadic form
- Children from family with no history of retinoblastoma
- Develop a single tumour in one eye - unilateral
Familial form
- Children with parent who suffered from retinoblastoma
- Develop multiple foci of tumours in both eyes - bilateral
– Elevated susceptibility of developing other tumours

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10
Q

What was Knudson’s 1 hit/2 hits hypothesis used for?

A

1971 – studied kinetics with which retinal tumours appeared in children affected by retinoblastoma

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11
Q

What were the results of Knudson’s 1 hit/2 hits hypothesis for retinoblastoma?

A

Rate of appearance of familial tumours - 1 single random event
Rate of appearance of sporadic tumours - 2 random events

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12
Q

Retinoblastoma is caused by a mutation in what gene?

A

Rb gene

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13
Q

What is needed to cause retinoblastoma in children with wildtype Rb from parents?

A

2 successive alterations in retinal cell lineage required to inactivate the 2 Rb copies

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14
Q

What is needed to cause retinoblastoma in children with mutant Rb from family?

A

Mutation of the other copy in enough to drive retinoblastoma

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15
Q

How does sporadic retinoblastoma occur?

A

Probability of both mutations occurring one after the other is 10-12 per cell generation
More likely to occur due to mitotic recombination

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16
Q

How can mitotic recombination cause retinoblastoma?

A

Chromosomal arm carrying WT Rb allele replaced with arm carrying mutant allele
Frequency of 10-5 - 10-4 per cell generation - easier than mutational inactivation
Loss of heterozygosity
- Heterozygous phenotype –> homozygous phenotype

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17
Q

What are the two possible ways tumour suppressor genes can stop cancer development?

A

Direct suppression of cell proliferation in response to growth-inhibitory and differentiation-inducing factors
Components of cellular machinery that inhibit proliferation in response to metabolic imbalance and DNA damage

18
Q

What are two of the most studied tumour suppressor genes?

A

Rb and p53

Role in control of the cell cycle disrupted in most human tumours

19
Q

What are the 3 examples of how tumour suppressor genes function in a diversity of ways?

A

NF1: negative regulator of Ras signalling
APC: negative regulator of b-catenin signalling
pVHL: negative regulator of HIF-1 transcription factors

20
Q

What is neurofibromatosis and what is it caused by?

A

Caused by LOH of NF1
Familial cancer syndrome
Benign tumours in PNS – some progress to malignant neurofibrosarcomas

21
Q

What is NF1?

A

Is a Ras GTPase activating protein

22
Q

What do mutations in NF1 cause?

A

Create a protein with 1000 fold decrease in GTPase stimulating activity

23
Q

What happens to NF1 if a cell is stimulated with growth factors?

A

NF1 degraded - enable Ras signalling to proceed

After 60-90min NF1 levels return to normal - shut down Ras signalling

24
Q

What happens when NF1 is lost in a cell?

A

Ras remains activated for longer

Loss of NF1 mimics hyperactivation of Ras observed in presence of mutant ras oncogenes

25
Q

What is APC and what does it facilitate?

A

Adenomatous Polyposis Coli

Facilitates the loss of cells from colonic crypts

26
Q

What cancers is APC found in?

A

95% of colon cancers - sporadic

1% inheritable adenomatous polyposis coli – familial

27
Q

What is inheritable adenomatous polyposis coli?

A

Susceptibility to develop colon polyps which are prone to develop into carcinomas

28
Q

Where are stem cells normally found in a colonic crypt?

A

Stem cells are found at bottom of intestinal crypts

  • Some progeny stay behind to maintain stem cells
  • Most progeny dispatched upward and out of crypt toward epithelium
29
Q

What is the defence mechanism found within the colonic crypt?

A

Out-migration and death takes 3 to 4 days

If cells get mutations, they die within days without damaging intestine

30
Q

What do APC mutations that drive cancer do?

A

Block the out-migration of cells from the crypt
B-catenin controls this process - B-catenin levels controlled by Wnt signalling
Mutated cells accumulate in the crypt rather than being lost

31
Q

How does APC control B-Catenin?

A

APC negatively controls B-catenin levels in the cytosol

32
Q

Where is APC expressed within the colonic crypt?

A

APC is not expressed in the cells at the bottom of the crypt

  • B-catenin can accumulate and move in the nucleus
  • As cells move upward APC expression increases
33
Q

What does inactivation of APC do?

A

B-catenin cytosolic accumulation and nuclear translocation
Transcription of growth-promoting genes - myc
90% of sporadic carcinomas caused by B-catenin accumulation

34
Q

Wild-type mice colonic crypts

A

Have small defined crypts in small intestine with little nuclear β-catenin at bottom of crypt

35
Q

What is the phenotype of APC -/- mice?

A

Show crypt-progenitor cell phenotype with increased crypt size and nuclear β-catenin

36
Q

What is Von Hippen Lindau syndrome?

A

Hereditary predisposition to the development of a variety of tumours

  • Clear cell kidney carcinomas
  • Pheochromocytomas - adrenal gland cell tumours
  • Hemangioblastomas - blood vessel tumours in CNS and retina
37
Q

What does VHL code for?

A

pVHL protein

38
Q

What is VHL?

A

Tumour suppressor gene

VHL gene inactivated in 70% of sporadic kidney carcinomas

39
Q

What is the function of pVHL?

A

Promote destruction of HIF-1a

Enables cells to survive hypoxia and acquire access to oxygen supply

40
Q

What are the target genes of pVHL?

A

Genes that lead to:
Angiogenesis
Erythropoiesis
Glycolysis and glucose uptake

41
Q

What are the two molecular mechanisms of inactivation of pVHL?

A

Mutant alleles of VHL - pVHL protein undetectable in cancer cells
Point mutations in amino acid residues in hydrophobic pocket recognising hydroxyproline residues in HIF-1a

42
Q

What does inactivation of pVHL lead to?

A

Constitutive activation of HIF-1 transcription factors

- Leads to growth promoting genes stimulating proliferation - tumour

Stem Cell and Cancer (15 decks)

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