Lecture 9 Flashcards

1
Q

P53

A

Tetrameric

Transcriptional Activator

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2
Q

P53 Null Cell line experiment

A
  • unable to induce tumour supressor genes
  • -Used Dexamethazone small molecule inducer
    to induce expression of wt p53
    -Isolate and compare mRNa
    -Convert it into DNA – hybridise the Combined DNa and carry out subtractive hybridisation to find nucleic acids not expressed in the first codniton but in the second
  • Main gene identified was in responses to Dexamethazone WAF1
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3
Q

What does WAF1 do ?

A
  • sequenced and compared to a database
  • P21 Cip 1
  • Cyclin dependent kinase inhibitors
  • inhibits the cdks involved in continuation of the cell cycel
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4
Q

Up regulation of P21 causes what

A

Cell cycle arrest

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5
Q

What happens in response to Gentoxic stresses in P53 mutants ?

A

Mutants cannot correct malfunction

- dont actually stop cell cycle&raquo_space; amplify the mistakes in proliferating cells

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6
Q

Levels of P53

A

induce distinctive genes depending on the error

- distinct program pathway

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7
Q

What processes does P53 induce when an error occurs ??

A
  • cell cycle arrest or Senescence/ return to proliferation
  • DNA repair
  • Block of angiogenesis
  • apoptosis
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8
Q

When do cells die?

A

When the amount of genomic damage is high and irreparable

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9
Q

What hallmark of cancer does P53 relate to?

A
  • very short half life

- Rate of synthesis of P53 and degradation is normally high

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10
Q

In a particular subset of mouse sarcomas what was found when addressing the question; What keeps P53 low ??

A

small set of gene products responsible for a particular phenotype in those sarcomas – double minute chromosomes (fish probes show one or two chromosome fragments when should be one)
- Gene identified as MDM which gives rise to this particular phenotype

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11
Q

MDM2

A
  • Directly involved in regulating P53 levels by binding directly
  • ubiquitin ligase catalyses ligation reaction and targets P53 for destruction in cytoplasmic proteasomes
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12
Q

MDM

A

itself a target of P53 and regulated

- causes continuous turnover/degradation of P53

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13
Q

P53 regulation

A

P53 has its own mechanism to regulate its levels

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14
Q

What keeps P53 levels up ?

A
  • ARf tumour suppressor
    Largely made only in S phase
    Exerts a regulatory control on the system above by binding /mdm2 so it cant access P53 and MDM2 is sequestered in the nucleus
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15
Q

Describe the diagram of the tumour suppression pathway before cell cycle arrest or apoptosis ?

A
E1A/ C-Myc/ Ras 
            I
         E2F
            I 
         ARF
          _I_
       MDM2 
          _I_ 
       P53 >>
Cell cycle arrest or Apoptosis
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16
Q

Genotoxic stress

A

increases P53 levels
-ATM/ATR are activated during genotoxic stress
And phosphorylate P53 > Cell cycle arrest/DNA repair/ Apoptosis

17
Q

ATM

A

-Monogenetic disease
-kids prone to getting cancer
-No cellular response to ionising radiation
Tissue necrosis

18
Q

ATM

A

gets turned on in response to double DNA stranded DNA breaks

19
Q

ATR

A

switched on when DNA replication is arrested

20
Q

Kinase part of ATM/ATR looks like

21
Q

Inactive forms of p53 enable

A
  • Oncogene activation without apoptosis
  • Higher tolerance of anoxia
  • Sloppy oversight of chromosome integrity
22
Q

P53 Re-activation provides potential new cancer treatment

A
  • Interact with P53 and change its shape
  • Move mutant version back to wt
  • PRIMA1 molecule
  • Cells start accumulating more freq in G2 spending more time in G2
  • Promote apoptosis with a molecule that binds to P53 and induces functionality
23
Q

The study of what led to the discovery of P53

A

of how oncogenic viruses subvert host cell control of DNA replication

24
Q

Wild-type p53

A

Is an unusual type of tumour suppressor gene

25
P53 summary
is mutated in a large proportion of human cancers, with a predominance of missense mutations
26
P53 null mice
develop normally but die prematurely of cancer
27
P53 is a shortlived protein
whose steady state level is controlled by regulated proteolysis
28
Genotoxic stresses
block p53 destruction and enable it to act as a transcription factor
29
P53 induces what ??
P53 induces the transcription of genes that arrest the cell cycle and induce DNA repair
30
Prolonged expression of p53 induces what ??
Prolonged expression of p53 induces apoptosis
31
Cancer cells
Cancer cells acquire selective advantages by acquiring mutant forms of p53
32
Future..
Future progress in cancer treatment might be obtained by novel drugs that can “reactivate” mutant, transcriptionally inactive forms of p53