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Cancer & Genetics > Advance cell signalling - p53 TSG > Flashcards

Advance cell signalling - p53 TSG Flashcards

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Biology 101 flashcards
1
Q

What virus is p53 associated with?

A

SV40 (Simian Virus 40) - binds to the SV40 T-antigen (antigen = also bound to antibody)

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2
Q

Location of p53 gene?

A

Chromosome 17 p13 (short arm of ch 17)

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3
Q

What is meant by p53 is a haploinsufficient gene?(+-)

A

-When have only 1 functional p53 allele = not enough to stop cancers forming
-Seen in people with Li-Fraumeni

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4
Q

Cause of Li-Fraumeni?

A

-Germline mut (in all body cells) - often missense to 1 allele = 1 base pair changed so 1 AA different
-Get mutant prot
= +-

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5
Q

How is p53 activated, & what it does?

A

-By significant cellular stress = signif DNA damage
= post-translational modifications = so acts as TF
-TF activates genes for apoptosis, cell cycle arrest, DNA repair

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6
Q

What are the 2 categories of post-translational modifications to p53?

A

-Stabilisation (inc activity & function)
-Degradation (keep p53 levels low so apoptosis, cell cycle arrest, DNA repair not activated when not needed)

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7
Q

Stabilisation of p53 gene by post-translational modifications vs making (transcribing) more of p53 gene - both enable response to stress?

A

-Faster
-Reversible (e.g. -Pi/CH3/acetyl)
-Less energy
-Stress dependent
-How many modifications occur depends on stress levels

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8
Q

4 types of p53 post-translational modifications of stabilisation & what proteins do these to p53?

A

-Phosphorylation = ATM (kinase)
-Acetylation = p300
-Methylation = SET9
-Sumoylation = PIAS

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9
Q

1 type of p53 post-translational modification of degradation & what protein do this to p53?

A

Ubiquitination = MDM2

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10
Q

When is stabilisation & degradation used as post-transcriptional modifications of p53?

A

-Stabilise = when is significant cellular stress/DNA damage (stress dependent)
-Degrade = when is normal/basal levels of cellular stress

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11
Q

Why is it important to have reversible post-translational modifications of p53?

A

-To revert back to normal/basal

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12
Q

How does differences in sites of phosphorylation, acetylation, methylation, sumoylation affect p53 as a TF?

A

p53 will regulate different genes dependent on what is necessary based on the level of cellular stress/DNA damage

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13
Q

Domains of p53 gene & what can bind to these?

A

-DNA binding domain (part acts as TF binds to DNA promotor) - DNA & SV40 T antigen (inhibits TF function)
-Transactivation domain - HPVE6 & MDM2 (ubiquitination)
-Tetra domain - p300 (acetylation)
-Basic domain - p300 (acetylation)

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14
Q

Location of conserve regions - conserved through evolution?

A

In DNA binding domain

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15
Q

When can p53 activate cell cycle checkpoints?

A
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16
Q

How does DNA repair/cell cycle arrest, apoptosis occur due to p53?

A

Cellular stress = stabilising post-translational modifications

17
Q

What does p53 do to cause cell cycle arrest in G1?

A

-p53 transcriptionally upregulates (as TF) CDKIs =
-Activates CDK inhibitors e.g., p21 = stops CDK phosphorylating Rb - Rb & E2F1 remain in complex = E2F1 can’t act as TF = no cyclin for next stage of cell cycle

18
Q

What does p53 do to cause cell cycle arrest in S?

A

p53 transcriptionally upregulates (as TF) = inhibits PCNA = protein need for DNA rep = so no DNA rep

19
Q

What does p53 do to cause cell cycle arrest in G2?

A

p53 transcriptionally upregulates (as TF) = activates GADD45 & 14.3.3σ = inhibit CDKs needed to progress from G2

20
Q

How is apoptosis generated from p53 activation?

A

p53 transcriptionally upregulates (as TF) = activates BAD, BAX & Fas = causes apoptosis

21
Q

Process of apoptosis?

A

-Cell shrinks as DNA & chromatin condenses
-Memb blebs = cell forms protrusions containing DNA & other cellular components
-Organelles disintegrate
-Nucleus & organelles collapse (more blebbing)
-Apoptotic bodies form
-Macrophages take up ABs & phagocytose
= controlled cell death - so no inflammatory response

22
Q

2 modes of apoptosis?

A

-Extrinsic (starts outside cell)
-Intrinsic (starts inside cell)

23
Q

Features of extrinsic apoptosis?

A

-Cell surface death rec mediated
-Cytokines involved (bind to recs)
-TNF alpha = inflammatory cytokine involved
-Paracrine - signal to die passes from cell to cell (A->B…)

24
Q

Features of intrinsic apoptosis?

A

-Starts in mitochondria
-Due to cells detecting DNA damage (e.g., from UV, chemicals, ROS)
-Often autocrine = contained within the 1 cell

25
Q

Regulation of intrinsic apoptosis?

A

-p53 transcriptionally upregulates (as TF) = activates BAD, BAX
-BAD & BAX = prots = cause pores/channels in mitochondria
=Cyt C exits mit
-So no ATP as Cyt C = for ETC
-No ATP = signals cell to die
-Cytc C binds to APAF1
-APAF1 activates CASP9 then CASP3
-CASPs = proteases - digest prots

26
Q

Process of extrinsic apoptosis?

A

-p53 transcriptionally upregulates (as TF) = activates Fas transmemb rec
-FasL (ligand) binds to Fas
-Fas activates DISC complex (FADD & CASP8)
-Then CASP3 activated
-CASPs = proteases - digest prots

27
Q

Why would apoptosis need to occur?

A

If DNA repair = unsuccessful - to prevent this damage from passing to daughter cells

28
Q

How is p53 levels kept to a normal/basal level?

A

MDM2 = accelerator (POG) - allows rep
p53 = brakes (TSG) - prevents rep

29
Q

What is the dog analogy in p53?

A

MDM2 = dog
p53 = owner - controls/regulates

30
Q

Why would deactivation of MDM2 be embryonically lethal?

A

p53 causes cell death (apoptosis) continually - cannot be stopped

31
Q

What is the autoregulatory feedback loop in p53 & MDM2?

A

-p53 TF = transcription upregulation/activation of MDM2
-MDM2 binds to p53 = complex
-Complex = degraded - levels of both kept low = equilibrium

32
Q

What happens to p53/MDM2 complex when is cellular stress?

A

Significant cellular stress = causes MDM2 to detach from p53 due to post-translational stabilising modifications (e.g., +Pi)

33
Q

How do therapeutics treat cancers with normal p53 (only in 50% of cancers)?

A

-Cancer Therapy = chemotherapy = causes DNA damage (cellular stress) = p53 responds - cellular arrest/apoptosis
-MDM2 inhibitors = no DNA damage needed - p53 is free to respond continually (not in complex w/ MDM2) = cellular arrest/apoptosis

34
Q

When are MDM2 inhibitors used?

A

-When normal (wild type) p53 remains - non-mutated = to activate p53
-When MDM2 is overexpressed (oncogenic) - as don’t want too much as p53 would remain in complex w/ so no DNA repair/cellular arrest/apoptosis (oversupression of p53)

35
Q

What does the axis of life involve?

A

Cancer & Genetics (4 decks)

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