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BS3003 > 16th Feb - p53 > Flashcards

16th Feb - p53 Flashcards

1
Q

When was p53 discovered?

A

1979

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2
Q

How was p53 identified?

A

Interacted with viral proteins:

  • SV40 large T antigen
  • E1B of Adenovirus
  • E6 of papilloma virus
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3
Q

How was it identified that p53 was a tumour suppressor?

A

Originally thought to be an oncogene. Performed genetic studies to identify as TS

ras + p53 deletion mutant –> cell growth
ras + p53 val-135 point mutant –> increased proliferation
ras + WT p 53 –> no cell growth

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4
Q

What is Li-Fraumeni syndrome?

A

A rare dominant inherited cancer syndrome where patients have mutations in TP53 gene

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5
Q

How was it demonstrated that p53 protects against cancer?

A

Genetic studies in mice
p53-/- die very fast (0% survival at 250 days), as they get tumours very fast
p53+/- start to die at about 300 days
p53+/+ have 100% survival at 500 days

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6
Q

What is the main form of regulation of p53?

A

Phosphorylation

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7
Q

Does p53 function as an oligomer?

A

Yes it functions as a homotetramer

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8
Q

How does p53 recognise target genes?

A

It recognises a 10 base pair consensus sequence

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9
Q

In which exons of p53 are the majority of mutations located?

A

5-8

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10
Q

Which amino acids of p53 are hotspots for mutation?

A

175
248
273

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11
Q

How is the haploid insufficiency of p53 explained?

A

Mutant subunits from the mutated chromosome, form part of the tetramer with unmutated p53 subunits, meaning that only 1/16th of the tetramers produced are wholly WT

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12
Q

What is the half life of p53?

A

20 minutes

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13
Q

What is the main role of p53?

A

To define the cellular responses to different kinds of damage

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14
Q

Do all of p53s functions work harmoniously?

A

Some are antagonistic and can occur simultaneously

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15
Q

Where does it carry out its function?

A

Mainly in the nucleus but also in the cytoplasm

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16
Q

How can p53 by activated?

A

The MDM2 binding region can be phosphorylated in a variety of positions to prevent binding to MDM2

17
Q

How does MDM2 inhibit p53?

A

MDM2 binds to p53 in a normal state and inhibits it by ubiquitination

This is reinforced by a negative feedback loop, as p53 targets the MDM2 gene, so if there is too much p53 MDM2 transcription will increase correspondingly

Disrupting this negative feedback loop, leads to a massive increase in p53

18
Q

What are the different functions of p53?

A

Cell cycle arrest
DNA repair
Angiogenesis Block
Apoptosis

19
Q

What are the downstream effectors of p53?

A 
p53 antagonist - MDM2 
Growth arrest - p21 cip1 and reprimo
DNA repair - p53R2, XPC, DNAPk
Regulators of apoptosis - BAX, PUMA, NFkB, APAF-1, Fas/APO1, Bcl-2
Anti-angiogenic - TSP-1
20
Q

What are the two main categories of p53s pro-survival functions?

A

Prevent apoptotic signaling

Anti-oxidant function at basal levels

21
Q

Outline the mechanism of p53 blocking apoptotic signaling

A

p53 activates:
p21 which inhibits CDK, E2F, ASK1, and Caspase 3
BTC inhibits CDK, thus allowing Akt to inhibit apoptosis
14-3-3-delta inhibits Bax, Foxo 3, YAP and ASK1 preventing apoptotic signaling

22
Q

What genes does p53 target to inhibit ROS production?

A 
SESN-1
SESN-2
MnSOD
ALPHA
GPX
TIGAR
23
Q

How is the response of p53 determined?

A

Believed to be based on the post-translational modification of p53 e.g. Phosphorylation of ser 56 –> apoptosis and acetylation on lys 320 –> survival

24
Q

What is the barcode model?

A

Proposed by Zmijewski (2008) the cell response of p53 is determined by a series of factors dependent on PTM. The amount/type of stress will partially determine the PTM.

Along with the level of p53, its localisation and co-factors/modifiers present

25
Q

What protein acts in opposition to MDM2, stabilising p53?

A

HAUSP which deubiquitinylates p53 increasing its stability and causing the induction of cell cycle arrest

26
Q

What are the different isoforms of p53?

A

p53beta
p53 gamma
delta133p53
delta40p53

27
Q

Some of the isoforms of p53 are overexpressed in cancer, what is the possible function of this?

A

Perhaps block p53 or increase survival function of p53

e.g. in breast cancer delta133p53alpha is OE

28
Q

What are the other family members of p53?

A

p63

p73

29
Q

What is the function of p63 and p73?

A

They help p53 to create a different combination of responses

30
Q

Outline the experiment to elucidate p63/p73 function and the conclusion of the experiment

A

KO studies in mice

p63 -/- –> developmental defects –> death
p73 -/- –> developmental defects
p63 +/- and p73 +/- –> increased predisposition to cancer

Therefore p53 needs both p63 and p73 to induce apoptosis

31
Q

List the other physiological roles of p53

A 
Ageing
Development
Stem cell regulation
Endurance
Fecundity
Sun Tanning
Neurodegeneration
Ischaemia
32
Q

What is the role of p53 in ageing?

A

Contributes to both ageing and longevity have been reported, this may reflect its regulation of ROS

33
Q

Give evidence for the role of p53 in development

A

Encephaly in Trp53-deficient mouse models

34
Q

What is the role of p53 in stem cell regulation?

A

Involved in controlling self renewal and quiescence in adult stem cells

35
Q

What is the role of p53 in fecundity?

A

p53 is an important activator of leukaemia inhibitory factor, which is required for implantation of blastocytes

36
Q

What is fecundity?

A

the ability to produce an abundance of offspring or new growth

37
Q

What is the role of p53 in sun tanning?

A

p53 induces the expression of pro-opiomelanocortin

38
Q

What is the role of p53 in ischaemia?

A

It can have a protective function in models of stroke, MI, kidney ischaemia and reperfusion injury

39
Q

Outline the role of p53 in metabolism

A

It enhances OXPHOS through SCO2 and fatty acid oxidation through GAMT
It inhibits GLUT, GLUT and TIGAR therefore inhibiting the Warburg effect

BS3003 (26 decks)

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