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MYC L10-11 Flashcards

1
Q

What is the translocation of Myc in Burkitts lymphoma and what does it do?

A

T(8;14)

Causes constitutive switching on of Myc in B cells

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2
Q

What type of gene is Myc?

A

A proto oncogene

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3
Q

Where was V-Myc first identified and how?

A

In a group of avian retroviruses that cause myelocytic leukaemia in chickens. Found through hybridisation studies and information from the src protein discovered as the transforming agent of RSV

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4
Q

How do viruses gain oncogenes?

A

By capturing them from normal cellular DNA

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5
Q

Three ways by which Myc causes oncogenic activation

A

Gene amplification
Chromosome translocation
Insertional mutagenesis (of V-Myc)
(Unlike other proto oncogenes which are activated by mutations)

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6
Q

What growth factors does Myc respond to?

A

Activated hormones, growth factors on their receptors including: ER, AR, PDGF, wnt
These activate secondary messengers such as src and ras
Which activate transcription factors such as notch

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7
Q

What percentage of tumours is Myc in appropriately expressed in?

A

30-40%

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8
Q

In culture what will de differentiated cancer cells do?

A

They will pile up but not form 3D structures

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9
Q

How does Myc transform primary fibroblasts?

A

Requires a second proto-oncogene or mutation ie Ras to transform cells.

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10
Q

What is the structure of Myc?

A 
MBI and MBII
TAD 
NLS
basic region
HLH 
LZ
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11
Q

What is the function of the leucine zipper in Myc?

A

Regularly spaced leucines that lie on one face of an α helix and can interdigitate with another helix. Suggests Myc diner interaction

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12
Q

How does Myc bind to DNA

A

K and R in the basic region can interact with the DNA backbone in the major groove

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13
Q

What is the role of the transactivation domain of Myc?

A

The TAD can confer activation of gene transcription to a heterologous DNA- binding domain

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14
Q

What parts of the Myc protien are essential for repression?

A

MBII and the bHLH-LZ

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15
Q

What transcriptional activators does Myc-max interact with?

A

Nuclear factor Y (NFY)
SP1
MIZ1

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16
Q

What are the two independent polypeptide regions of Myc?

A

The N-terminus transactivating region

C-terminus DNA binding segment

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17
Q

How was max the Myc heterodimer discovered?

A

Screening of E.coli based cDNA libraries using the bHLHLZ region of c-Myc (that was labelled). Take labelled colonies and expand and isolate max

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18
Q

What does Myc-max bind to in DNA?

A

The E box.
A palindromic 6nt sequence
CACGTG

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19
Q

Structural hierarchy of chromatin

A 
Naked duplex DNA
beads on a string 
30nm fibre
Extended chromosome 
Condensed chromatin
Chromosome (mitosis only)
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20
Q

Nucleosomes are remodelled through?

A

Covalent modifications

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21
Q

What is GCN5?

A

A HAT conserved bromodomain with a lysine targeting motif approx 160 residues

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22
Q

P300/CBP is a

A

HAT bromodomain with 3x C/H rich domains

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23
Q

What does the addition of an acetyl group cause?

A

Electrostatic effects, neutralises the charge difference between the DNA backbone and the histone tails.

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24
Q

Where does a HAT source the acetyl group from?

A

CoA-SCH3O

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25
How does the HDAC remove the acetyl group?
Using H20
26
What are the two types of chromatin remodellers
ATP dependent and covalent
27
ATP-chromatin remodellers use ATP to...? (2)
1. Slide nucleosomes along the DNA to make gaps of naked DNA 2. Remove the nucleosomes from target DNA (it will immediately re-associate with another stretch of DNA) OCTOMER TRANSFER
28
What families of ATP-dependent chromatin remodellers are there in eukaryotes and what are their active subunits? (4)
SWI/SNF - BRG1 ISWI - ISWI NuRD - Mi2 INO80 - Ino80
29
When DNA is tightly compacted it is said to be
Condensed or occluded by nucleosomes and higher order chromatin structures
30
Give an example of pioneer activators and what they do.
When DNA is very condensed not many proteins can access it. But pioneer activators can. For example FoxA or GATA which acts either by enhancing transcription by reducing the number of factors recruited the DNA or by actively opening up local chromatin making it component for other factors to bind. FoxA moves much slower in nuclear chromatin than other factors suggesting unusually tight binding
31
Pioneer activator mechanisms
ATP- dependent and has covalent factors required to open up the DNA. They clear space of secondary activators to bind and recruit RNA pol II. Pol II then attaches and modifies nucleosomes as it tans locates along the DNA. Pol II has chromatin modifiers in its complex and continues to create naked DNA
32
In the PIC what state is the CTD tail in?
Unphosphorylated
33
The PIC causes the DNA to do what?
Melt and provide a transcription bubble which gives a template for the polymerase
34
How many repeats is the CTD in humans and yeast!
Humans - 52 | Yeast - 26
35
What type of repeat is the CTD?
A heptad repeat
36
What happens to the CTD to allow initiation and elongation of the pol II
Phosphorylation Of Ser5 by TFIIH to initiate RNAPII Then of ser2 by pTEFb to trigger pause release and elongation Dephosphorylation of ser5 by ser5 ppase leads to termination of RNAPII
37
PTEFb is targeted by what viral protein?
TAK an HIV transcriptional regulator
38
How to tell where in the DNA your target protein is binding?
ChIP-seq chromatin immunoprecipitation and high density sequencing
39
Process of ChIP-seq
1. Use formaldehyde to cross link proteins to DNA 2. Shear DNA to 100bp frags 3. Use antibody specific to protein of interest and purify by immuno precipitation 4. Remove cross link and digest the protein so only DNA that protein was bound to is present 5. Sequence library and get lots of sequences of where protein was bound to DNA
40
Chip-seq of RNA pol II showed?
RNA pol II only on active genes generally stalled at the 5' end and then moved rapidly across the gene and the brief stalling at the 3' end whilst processing occurs On inactive genes - pol is stalled at the 5' end
41
Without ser2p what does pol II binding look like?
Active genes Stalling at the 5' end, little binding across genes and no stall at the 3' end. No elongation trigger. Myc is involved at this stage On inactive genes: small amount of RNA pol at the 5'
42
RNA pol II binding with no ser5p
No detectable mRNA on productive or non productive genes
43
When is the 5' cap added and what is its role?
On pausing of pol, the mRNA is long enough to add the cap and acts as a label for translator machinery
44
The ser5p causes what
Promoter proximal pausing after promoter escape
45
NELF and DSIF are recruited to the RNAPII when?
After promoter clearance. | NELF is negative elongation factor and DSIF is DRB sensitivity including factor
46
PTEFb induces pause release by?
Phos of ser2 Phos of NELF (causing it to dissociate) Phos of DSIF and recruitment of ELL, eking in and TFIIF.
47
What are inactive genes waiting for?
Ptefb to come and release the complex and initiate puss release
48
What is ptefb in gene expression?
The rate limiting step/determinant
49
Give 5 stages of transcriptional regulation:
1. Chromatin modification by covalent modifications ie acetylation 2. ATP-dependent chromatin modifiers 3. Assembly of the pre initiation complex 4. Transcription initiation 5. Transcriptional pause release
50
In Myc what does the CTD interact with and to do what?
The transactivation domain interacts with the CTD to achieve high affinity and specificity to two structurally and functionally orthogonal targets
51
Where does TRRAP bind to Myc and what is it essential for?
Binds to MBII and is essential for transformation activity of Myc. Myc recruits histone acetylation complexes through TRRAP such as GCN5 containing SAGA complex.
52
What are the structural components of max?
An HLH and LZ | NLS
53
What else does max dimerise with?
Mad
54
Mad characteristics
Mad heterodimerises with max but not Myc It is involved in transcriptional repression by a sin3 interaction domain (SID) It also contains an bHLH and an LZ
55
Mad KO Myc KO Max KO
Mad - no differentiation or apoptosis. Cell stopping doesn't happen Myc - lethal, no proliferation Max - also lethal as Myc cannot act without max
56
When are Myc, mad and max expressed?
Myc - in non senescent cells (proliferating cells) Mad - in resting cells (non proliferative) Max - constitutive expression. On all the time in every cell
57
How does mad repress?
Mad and max bind to the e box | Sin3 recruits HDAC ½ resulting in repression
58
What has been shown to regulate the mad-Myc relationship?
VDR Causes the suppressed expression of cmyc and increased expression of mxd1 in vivo and inhibition of Myc regulated genes in virtro
59
In VDR -/- mice c Myc is?
Widely elevated
60
How can Myc max repress some genes?
Binding through MIZ1 and inhibits NPM a recruited cofactor. Myc induces apoptosis through this interaction by repressing the expression CDK inhibitor p21.
61
4 ways in which Myc can influence transcription
1. TRRAP and HAT 2. SWI/SNF recruitment 3. Ptefb + mediator 4. MIZ1
62
What happens to Myc in the absence of TGFβ? | What happens to Myc in the presence of TGFβ?
Myc represses CDKN2B by binding MIZ1 And displaying MIZ1 cofactors to silence the gene. With TGFβ Myc expression is suppressed and SMAD TF translocation ans cooperates with MIZ1 to recruit NPM1 as a MIZ1 cofactor. This stimulates transcription and induces cell cycle arrest.
63
How does Myc inhibition affect RNA pol II occupancy?
It inhibits gene expression and there is a queue up of RNAPII at the 5' end. The same effect is observed in ptefb inhibition. This is because Myc recruits ptefb and ptefb is required at all gene to get through pausing. If Myc is present then ptefb acts through Myc. Is Myc is not present the ptefb acts independently
64
Where are a significant proportion of Myc binding sites?
In the first introns of genes
65
Can Myc influence pol I and pol III?
Yes.
66
How does Myc affect pol III?
By binding to TFIIC/B and recruiting GCN5 a very specific HAT
67
How are pol I and III different to II
They don't have a CTD (acts on I very similarly to II)
68
Myc interacts with what protein at pol I targets and recruits what?
SL1 and recruits HATs via TRRAP
69
What functional categories of genes does Myc modulate?
``` Protein biosynthesis Metabolism Transcription factors and cell cycle MiRNA Inhibits CDKs ```
70
How does Myc affect ribosomes in division?
Myc drives ribosome tRNA biogenesis
71
What is p53?
A tumour suppressor gene
72
p53 is involved in what processes?
Repair, growth arrest, apoptosis, transcription
73
What is the p53/mdm2 relationship?
DNA damage - mdm2 decrease - increase p53 - increase mdm2 | Mdm2 degrades p53 and p53 synthesises mdm2
74
Role of ARF
A TSG that inhibits mdm2 and activates p53 | A self checker
75
What modulators have been found that regulate the ARF-mdm2-p53 axis?
BMI1, TWIST1 and CUL7 which can cooperate with Myc in human disease
76
How can Myc affect the anti-apoptotic bcl2/xl
By indirect suppression
77
What does Myc do to the pro apoptotic bax?
It triggers a conformational change that activates the pro apoptotic protein bax directly influencing cytc release from the mitochondria and the downstream effector caspases
78
Myc can trigger two types of apoptosis
P53 dependent and p53 independent (by up regulation of pro-apop BIM shown by Cory et al that Eμ-Myc-BIM null and Eμ-Myc;BIM haplosufficient mice quickly developed lymphomas without activating p53 TSG pathway)?
79
What miRNAs is mc affected by?
Let7, mir34 and mir135
80
How does max affect the structure of Myc?
Causes more complex folding and more structure on dimerisation
81
Half life of Myc?
15-20mins
82
How is the transactivation of Myc regulated?
By phosphorylation of ser62 then thr58 then proteosomal degradation post function
83
Myc can be cleaned by what to form myc-Nick and what does this do?
Myc is cleaved by calpains in a Ca2+ dependent manner this removes the NLS and produces a stable product which can recruit GCN5 and cause acetylation of αTubulin this promotes differentiation in a non-transcriptional manner
84
Myc may function without max but...
It binds to other HLH proteins
85
What miRNA does Myc activation?
The miR17-92 cluster. Which when stim my Myc affects E2F activity and TGFβ signalling pathways.
86
How does Myc promote G1/S?
By regulating cyclin E CDK2 in parallel to classical pRb/E2F
87
What happens to g1 in cells with activated Myc?
It is often shortened
88
How does Myc affect the cell cycle?
It abrogates the transcription of the cell cycle checkpoint genes and inhibits CDK inhibitors Activated cyclins and some CDKs and e2f1/2
89
What happens to Myc to exit the cell cycle
It is down regulated and induction and function of the mxd family members occurs in response to differentiation cues
90
Deregulated Myc causes:
Migration promotion and features of aggressive less differentiated aand metastatic cancers Angiogenesis (shown by Thomas-Tikhonenko) is caused by Myc promoting miR17-92 degradation of thrombospondin (required for angiogenesis)

DG & EC (6 decks)

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