19.06.01 Tumour suppressor genes Flashcards

1
Q

What are tumour suppressor genes

A

-Encode proteins that prevent inappropriate cell growth and division and stimulate cell death. Their loss/inactivation gives rise to malignancy

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2
Q

What are the three tumour suppressor genes subgroups

A
  • Gate keepers: encode proteins that control the cell cycle and regulate cell proliferation (p53, APC, Rb)
  • Caretaker genes: maintain and protect the integrity of the genome. Involved in DNA repair and prevent accumulation of mutations (MLH1, MHS2)
  • Landscaper: help create environments that control cell growth. Loss of these cause the microenvironment to become abnormal and promote transformation of normal epithelial cells (e.g. PTEN)
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3
Q

Mechanisms to control cell growth and division

A
  • Restrain cell growth. Either by controlling progression within the cell cycle. Or inhibit proliferation.
  • Maintain integrity of genome
  • Stimulate cell death
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4
Q

Retinoblastoma

A
  • Aggressive childhood cancer of the eye.
  • Can be unilateral or bilateral
  • Incidence= 1 in 15,000/20,000 live births.
  • 10-20% are large structural variants
  • 80-90 single base substitutions or indels
  • LOF associated with complete penetrance and severe phenotype compared to missense.
  • 60-70% tumour exhibit loss of heterozygosity with a mutation in the other allele.
  • third of retinoblastomas are hereditary
  • Rb gene, 13q14
  • Encodes pRB as nuclear phosphoprotein
  • Protein pock family. Pocket is a conserved protein interaction domain that acts as a transcriptional repressor.
  • Role in cell cycle progression, chromosome stability and regulation of apoptosis
  • phosphorylated by CDKs, becoming inactive. E2Fs are then release to activate transcription, leading to cyclin E production and entry into S phase.
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5
Q

What is knudson’s two hit hypothesis

A
  • Discovered by studying retinoblastoma and differences between sporadic and hereditary RB
  • Both forms require two hits to RB gene.
  • Hereditary form: a mutant allele is inherited. Later a somatic mutation inactivates the normal allele leading to disease development. Variable penetrance.
  • Sporadic form: 2 somatic events occur. Second hit must occur in descendants of cell with first hit. Second mutation could be LOH, promoter methylation (gene silencing), mutation or deletion.
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6
Q

What does p53 do

A
  • Central component of signalling pathways essential for cell growth, regulation and apoptosis.
  • Induced by non-genotoxic stresses (oxidative stress, hypoxia, double strand breaks)
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7
Q

What regulates p53 levels

A

MDM2 (E3 ubiquitin ligase). When phosphorylated it migrates to nucleus and binds to p53, causing it to be degraded by ubiquitin pathway.

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8
Q

Causes of loss of p53

A
  • Mutations in gene upstream of p53, p53 cannot be activated. e.g. ATM, CHK2.
  • Mutations in p53 (50% of tumours have somatic variants in p53). Li-Fraumeni syndrome cause by p53 germline mutations.
  • Mutations downstream of p53. e.g. PTEN. Cowden syndrome.
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9
Q

What does CDKN2A regulate

A

RB and p53

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10
Q

What does CDKN2A encode

A

p16INK4A (inhibits RB) and p14ARF (inhibits p53)

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11
Q

Can microRNAs function as TSGs?

A

Yes. Can be used as markers of disease, prognosis, therapeutic targets. Interact with p53

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12
Q

Example of a tumour suppressor miRNAs

A
  • miR-34 family.
  • Lost in lung cancer.
  • miR-34a promotes p53-mediated apoptosis
  • Required for radiation response
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