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Cancer and genetics > Advanced Cell Signalling > Flashcards

Advanced Cell Signalling Flashcards

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1
Q

What is p53?

A

Tumour suppressor protein

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2
Q

Structure of p53

A

53kDa protein co-immunoprecipitated with a large SV40 T antigen

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3
Q

What is SV40 large t antigen?

A

Viral protein required for viral DNA replication

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4
Q

SV40 transform cells

A

Large T antigen forms a complex with p53 (53kDa) protein

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5
Q

What happens when SV40 T antigen binds to p53?

A

Inactivates p53

This causes the cells to leave G1 phase and enter into S phase, which promotes DNA replication.

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6
Q

What chromosome is p53 found on?

A

17

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7
Q

Where on the chromosome is p53 found?

A

Short (p) arm of chromosome 17 at position 13

17p13

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8
Q

Whats p53 known as?

A

Guardian of the genome

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9
Q

Li fraumeni syndrome

A

Germline mutation in p53

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10
Q

What happens when p53 is mutated?

A

Reduced (attenuated) tumour suppressor function

Increases your risk of cancers e.g neuroblastoma

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11
Q

p53 mutation rate in cancers

A

50% of cancers

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12
Q

What type of mutation occurs in p53?

A

Missense- nucleotide changes so codon codes for a different amino acid
High levels of non-functional protein

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13
Q

p53 mutation effect on chemotherapy

A

p53 mutation causes poor response to chemotherapy

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14
Q

What activates/upregulates p53 activity?

A

Cell stress e.g DNA damage by mutagen/UV/radiation/chemical damage

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15
Q

How does p53 respond to DNA damage?

A

p53 induces target genes

target genes= repair DNA, cause cell cycle arrest (p21) and apoptosis (BAX)

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16
Q

Structure of p53

A

400 amino acids in length
1st 100 amino acids= transactivation domain
Next 200 amino acids= DNA binding domain
Final 100 base pairs= Tetramerization gene

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17
Q

What happens in the transactivation domain?

A

Transcriptional machinery binds to p53 here

MDM2 (mater regulator of p53) and HPVE6 binds here too

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18
Q

What happens at the DNA binding domain?

A

p53 binds to DNA here
allows p53 to interact with nucleotides in promoters to bind and transactivate its target genes
SV40 (tumour antigen) also binds here

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19
Q

Where do 95% of mutations p53 occur in?

A

DNA binding domain

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20
Q

Effect of mutation in DNA binding domain of p53?

A

Will affect p53 function and ability to induce target genes in response to DNA damage

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21
Q

What occurs at tetramerization gene?

A

Interacts with other p53 based proteins that can regulate p53 e.g p300

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22
Q

What are DNA contact mutants

A

Mutants which establish contact with DNA by forming Zn fingers
Can change DNA conformation

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23
Q

What are structural mutants?

A

Alter structure of central domain of p53

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24
Q

In the cell cycle what does p53 regulate in response to DNA damage?

A

Cell cycle checkpoints

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25
Q

How does p53 regulate cell cycle in response to DNA damage?

A

P53 can halt DNA damage at G1-S phase, S-G2 phase and G2-M phase

26
Q

What happens when DNA is damaged by UV?

A

P53 is massively upregulated
p53 induces expression of genes in cell cycle that will stop genes that have damaged DNA progressing through cell cycle
Prevents daughter cells being formed with mutation in that gene
Stops cells dividing that have damaged DNA

27
Q

What induces apoptosis?

A

p53

28
Q

How does p53 induce apoptosis?

A

p53 binds to pro-apoptotic genes and genes involved in apoptosis

29
Q

What happens to a cell in apoptosis?

A
  1. cell shrinks and chromatin condenses
  2. Membrane starts blebbing
  3. Organelles disintegrate
  4. Nucleus and organelles collapse
  5. DNA undergoes fragmentation
  6. Cell breaks down into apoptotic bodies but membrane remains intact
  7. Apoptotic bodies are phagocytosed by macrophages
30
Q

Regulation of apoptosis

A

Highly controlled and tightly regulated

31
Q

When is apoptosis deregulated?

A

Embryogenesis and normal development

32
Q

How is apoptosis involved in the immune response?

A

Apoptosis of neutrophils and lymphocytes once they have been exhausted in the immune response

33
Q

2 Types of apoptosis

A

Extrinsic and Intrinsic apoptosis

34
Q

What is extrinsic apoptosis?

A

Signal that activates apoptosis comes from outside of cell
Mediated by cell surface death receptors
Cytokine/ligand dependent
Involved in inflammation

35
Q

What type of signalling is extrinsic apoptosis an example of?

A

Paracrine

36
Q

Extrinsic apoptosis pathway

A
  1. Stimulus= ligand
  2. Ligand binds to FAS (cell surface death receptor)
  3. Causes formation of DISC complex= FADD+CASP8
  4. This induces CASP3
  5. Casp3 causes apoptosis - rapid cell death
37
Q

What are caspases?

A

Proteases involved in apoptotic pathway

38
Q

What is the intrinsic apoptosis pathway?

A

Signal that activates apoptosis comes from inside of cell

Transcription of genes due to DNA damage by UV/radiation

39
Q

Intrinsic apoptosis pathway

A
  1. Signal comes from inside of cell
  2. p53 bound to promoter in nucleus
  3. Causes expression of pro-apoptotic genes e.g BAX and BAD
  4. Causes pores to form in mitochondrial membrane= mitochondrial transformation pores
  5. pores release Cytochrome C from mitochondria
  6. Cytochrome C binds to APF-1
  7. This induces Casp9
  8. Cytochrome C, APAF-1, CASP9 complex= apoptosome
  9. CASP9 binds to induce CASP3
  10. CASP3 induces apoptosis
40
Q

Post-translational modification of p53

A

p53 binds to basal targets

Induces activation of genes involved in DNA repair and growth arrest

41
Q

What does acetylation of p53 result in?

A

Growth arrest and DNA repair

42
Q

What does p53 induce?

A

p21

43
Q

What does p21 do?

A

causes G1 cell cycle arrest

44
Q

What happens when cells in hair follicles are no longer needed?

A

Induction of p21= G1 cell cycle arrest

45
Q

Retinal cells

A

Cells have no expression of p21

But will still undergo apoptosis

46
Q

p53 tumour suppressor gene= brakes?

A

Prevents cell replication and division during normal cell proliferation

47
Q

What are proto-oncogenes?

A

Normal genes that allow cell replication e.g growth factors and receptors

48
Q

Brakes vs accelerator

A

Important to have a balance between p53 (brakes) and proto-oncogenes (accelerators)

49
Q

What is MDM2?

A

Master regulator of p53
keeps p53 under control
MDM2 feeds back via an autoregulatory loop=to reduce levels of p53 in the cell

50
Q

What happens when MDM2 binds to p53?

A

Induces MDM2

p53-MDM2 complex= degradation of both proteins

51
Q

What are the signals that control activities of MDM2 and p53?

A 
NLS= Nuclear localisation signal
NES= Nuclear exporter signal
NoLS= Nucleolar exporter signal
52
Q

What does signal NES do?

A

Helps export p53 and MDM2 in and out of cells

53
Q

NoLS

A

Important in function of MDM2

54
Q

How is p53 inactivated?

A
  1. p53 moves into nucleus
  2. p53 binds to promoter regions of genes it induces
  3. p53 links up with MDM2
  4. p300 binds to p53-MDM2 complex
  5. Causes it to be acetylated
  6. This targets for p53 degradation via proteasome pathway
55
Q

What regulates MDM2?

A

p14ARF

56
Q

Which oncogenes induce p14ARF?

A

Myc and Ras

57
Q

How does p14ARF control MDM2?

A

ARF of p14ARF binds to MDM2
Removes MDM2 away from p53
MDM2-p14ARF travel into nucleolus
Leaves p53 alone to transcribe important genes e.g for DNA repair

58
Q

What happens if p14ARF is inactivated/silenced in a tumour?

A

Deregulation of p14ARF= deregulation of p53

59
Q

Myc and ras

A

Mutated in 30% of cancers

60
Q

What is p14ARF

A

A tumour suppressor gene

Cancer and genetics (3 decks)

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