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Eukaryotic Gene Expression > L7 - Txnal Regulation of oncogenes and tumour suppressors > Flashcards

L7 - Txnal Regulation of oncogenes and tumour suppressors Flashcards

1
Q

What does inheritance of one inactive RB allele give?

A

90% chance of developing retinoblastoma at any early age after somatic mutation of second allele

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2
Q

What is mutation of RB gene also common in?

A

Many tumour types
Almost all small cell lung cancers
In cervical cancers RB neutralised by E7 from HPV that binds to the pocket of RB

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3
Q

What is the structure of the RB pocket?

A

Two subdomains each resembling a cyclin fold that interact to form a single domain

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4
Q

What is the structure of the rest of RB?

A

N terminal domain has cyclin folds
Rest unstructured and flexible
C terminal bound by protein phosphatase 1 and CDK 2,4,6

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5
Q

What happens to RB in G1 phase?

A

Hypophosphorylated by cdk4 and cdk6 +cyclin D committing cell to leave G1 (restriction point)

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6
Q

What is the function of cyclin D in the cell cycle/

A

Expressed in response to mitogens - RB therefore couples cell cycle entry to mitogenic signals (gatekeeper)

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7
Q

What happens to RB in S phase?

A

cdk2/cyclin E phosphorylate further and inactivate RB

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8
Q

What happens to RB in G2?

A

cdk2/cyclin A maintains phosphorylation and inactivation

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9
Q

What happens to RB in M phase?

A

Phosphorylation reversed by protein phosphatase 1 (PP1)

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10
Q

What happens when RB is hypophosphorylated?

A

cells remain in G1 or withdraw into a quiescent state

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11
Q

How can some cancers subvert Rb?

A

Neutralise by binding of oncogenic protein to pocket domain or switched off by phosphorylation

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12
Q

How can cancers hypophosphorylate RB?

A

Overespress Cyclin D and ckd4

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13
Q

What is the function of INK4?

A

Encodes p16 and p15 that bind to cdk4 and 6 blocking action so cant bind to cyclin D

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14
Q

How is INK4 involved in cancer?

A

When INK4 genes deleted (melanoma) this deregulates RB phosphorylation

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15
Q

What TFs does RB regulate?

A

MyoD, UBF, TFIIIB, E2Fs

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16
Q

What are E2Fs involved in

A

Regulate DNA syn genes and cyclin E gene

Recruits TFIID to promoters

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17
Q

How does RB regulate E2Fs?

A

Binds txn action domain
RB recriots HDACs and chromatin remodellers to repress E2F
Phosphor of RB causes release

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18
Q

What do activator E2Fs do?

A

Txn activators during cell cycle progression and most abundant in proliferating cells

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19
Q

What do repressor E2Fs do?

A

Expressed in quiescent cells, inhibit E2F target genes

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20
Q

How is RB involved in pol 3 txn?

A

Hypophos RB binds to TFIIIB and blocks interactions with C + pol 3
So RB can block all pol 3 txn

21
Q

What other proteins have pocket domains?

A

p107 and p130 (54% identical to each other and 25% identical to RB)

22
Q

What is a characteristic of p107 and p130 and how is this involved in cancers?

A

Can be switched off through phosphor

So a lot of cancers lose function of all 3

23
Q

What is ARF>

A

E2F target

One of 3 tumour sup genes in a 35kb region often deleted in tumours

24
Q

How does ARF work?

A

Induced by oncogenic signals
Binds MDM2 and inhibits ubiquitin ligase activity
Triggers p53 response

25
Q

What does pol 1 do?

A

Syntehsise 18S, 5.8S and 28S rRNA as large precursor transcript

26
Q

How does ARF affect the activity of pol 1?

A

Inhibits processing of S’s rRNA

27
Q

What are free ribosomal proteins and example of one?

A

Released by imbalances in ribosome biogenesis (nucleolar stress) eg RPL11

28
Q

What can RPL11 do?

A

Bind and inhibit MDM2 - activating p53

29
Q

What does activating p53 do during nucleolar stress?

A

Provides important checkpoint to prevent cell cycle progression when ribosome production is inaequate

30
Q

What are p53super mice and what did they show?

A

Extra copy of p53 inserted in

Reduced cancer incidence

31
Q

What does loss of RB function cause in cancers?

A

Induction of ARF and hence p53 leading to oncogenic stress

32
Q

How does HPV cause cancer?

A

Encodes oncogenincE7 that binds and neutralises and E6 targets p53 for ubiquitination and degradation - causing cervical cancer

33
Q

How does SV40 DNA tumour virus cause cancer?

A

Large T antigen binds and neutralises RB and p53

34
Q

What is the incidence of loss of p53 in all cancers?

A

Over 50% (highest of all known genes)

35
Q

Where is p53 usually mutated?

A

DNA binding domain

36
Q

What do MDM2 and MDMX do?

A

Bind txn domain of p53 (mono export, poly degrade)

Both bind and inhibit RB

37
Q

What do intentional mutations of p53 in mice show?

A

Knock in - prevents induction of apoptosis but not tumour suppression
p53 mutants able to induce cell cycle arrest and apoptosis, but not supress tumour

38
Q

What occurs in Brukitt lymphoma?

A

Chromosomal translocations place MYC under control of an Ig enhancer

39
Q

How does MYC generally act?

A

Stimulates txn of open genes rather than inducing silent ones

40
Q

How does the way MYC usually acts cause cancer?

A

May amplify other oncogenic TFs

contrasts normal assumption that oncogenic transformation involves switching key genes or or off

41
Q

How did they show what genes MYC activated and repressed?

A

Model cell line carrying MYC transgene controlled by a doxycycline-activated promoter

42
Q

What genes did they show MYC activated and repressed?

A

Increased pol2 occupancy at KLF15

Reduced pol 2 occupancy at ALDJ3B1

43
Q

How can repression by MYC sometimes work and give an example?

A

Involving interference with other activators

Miz1 activates p21, but MYC blocks interaction with p300

44
Q

How is MYC involved with pol1?

A

DNA sites recognised by MYC found in rRNA promoters, binds and stimulates txn but recruiting SL1 and HATS

45
Q

How is MYC involved with pol3 txn?

A

MYC recruited by TFIIIB where it then recruits HATs to stimulate txn

46
Q

What does the action of MYC have to do with cancer?

A

Involved in all protein synthesis required for tumour growth

47
Q

How did they show MYC induced increased protein synthesis?

A

Used MYC overexpresser in mice B cells, stimulated protein syn and size of b cells
Then crossed with a lower translating mutant (L24) and reverted to normal (control)

48
Q

What was a therapeutic option for MYC driven cancers?

A

L24 decreased lymphomagenesis suggesting MYC needs to increase rate of protein syn to cause lymphomas

Eukaryotic Gene Expression (8 decks)

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