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Advanced Cell Signalling > Control of Immediate Early Gene Transcription > Flashcards

Control of Immediate Early Gene Transcription Flashcards

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1
Q

What is the activation of a signalling pathway?

A

Transient

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2
Q

What are the effects of signalling pathway activation?

A

Transient or long term

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3
Q

What is the usual half life of most proteins?

A

Less than 24 hours

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4
Q

How can the output be varied by activating a signalling pathway?

A

Amplitude
Duration
Sub cellular location
Context

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5
Q

What are PC12 cells?

A

Cell line derived from rad adrenal medulla

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6
Q

What do PC12 cells response to?

A

NGF and EGF

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7
Q

What do NGF and EGF activate?

A

The classical ERK1/2 MAPK cascade

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8
Q

How do NGF and EGF act differently in PC12 cells?

A

NGF activates ERK1/2 for longer
EGFR is internalised faster
NGF promotes stronger nuclear activation of ERK1/2
NGF activates Rac1 at the membrane, EGF does not do this well
NGF causes neuronal differentiation, EGF induces proliferation

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9
Q

What causes the difference in NGF induced neuronal differentiation and EGF induced proliferation?

A

The different in ERK activation

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10
Q

How does NGF increase ERK1/2 nucleur activation?

A

ERK1/2 has to translocate from the cytoplasm to the nucleus and therefore the longer the activation, the more ERK can translocate

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11
Q

What is gene transcription controlled by?

A

Transcription factor recruitment / activation of gene promoter
Chromatin environment

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12
Q

How does transcription factor recruitment / activation of gene promoters effect gene transcription?

A

Promoters can be regulated by multiple transcription factors
Multiple pathways converge on one transcription factor

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13
Q

How does chromatin environment effect gene transcription?

A

Chromatin structure can be stably modified during cell development or after cell stimulation
- e.g. methylation allows you to have open and closed areas for chromatin (closed inhibits transcription)
This changes promoter exposure

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14
Q

How are immediate early genes induced?

A

quickly after stimulation

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15
Q

What do immediate early genes not need which secondary response genes do?

A

Synthesis of new proteins e.g. transcription factors

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16
Q

What is IL-10 and why?

A

An immediate early gene

It is transcribed quickly after activation and cyclohexamide does not effect its transcription

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17
Q

What cyclohexamide do?

A

Inhibits the production of new proteins

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18
Q

What is IL-6 and why?

A

A secondary response gene

It is produced slower than IL-10 and is inhibited by cyclohexamide addition

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19
Q

Give example of transcription factors which are immediate early genes

A

c-fos
c-jun
nur77

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20
Q

Give an example of an immediate early gene which modifies the cytoskeleton

A

Arc

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21
Q

Give examples of enzymes which are immediate early genes

A

iNOS

PTGS2/ cox2

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22
Q

Give examples of cytokines/ growth factors which are immediate early genes

A

IL-10
IL-1
HB-EGF

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23
Q

How does phosphorylation control transcription factors?

A

It promotes cytoplasmic location in some cases

Can also promote nucleur location

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24
Q

Give an example of how phosphorylation induces cytoplasmic location

A

Akt induces FOXO phosphorylation which causes 14-3-3 binding and cytoplasmic location
Inhibition of Akt induces FOXO movement into the nucleus for transcription

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25
Give an example of how phosphorylation causes nuclear location
JAK causes phosphorylation of 2 STAT molecules | The STAT molecules dimerise and move into the nucleus
26
Describe CREBs function
Promotes immediate early gene transcription which causes: - development - regulation of metabolism - synaptic function - Innate immune function
27
What is CREB?
A transcription factor
28
What family is CREB a member of?
bZIP
29
What are bZIP domains?
DNA binding domains with alpha helical motifs containing a sequence specific DNA binding region and a leucine zipper which mediates dimerisation
30
In DNA, what does CREB bind to?
cAMP response element (CRE)
31
Why are not all CRE's active?
They may be inaccessible - tightly bound to the nucleosome or in condensed chromatin Binding of TFs to adjacent sites may block CREB binding to CRE Motif may not be in the gene promoter or be able to contact the transcriptional machinery
32
As well as the bZIP domain, what are the other CREB domains?
Q1 KID Q2
33
What is a Q1 domain?
Glutamine rich domain
34
What is the KID domain?
Kinase rich domain
35
What is CREM?
It only has a Q2 and bZIP domain and therefore still binds CRE but cannot drive transcription May be a CREB inhibitor
36
What is ATF1's relation to CREB
They have similar structures and are regulated in a similar way and therefore may compensate for one another
37
What is the PKA signalling pathway
GPCR -> GalphaS subunit -> Adenylate cyclase -> cAMP -> PKA
38
What inhibits cAMP?
Phosphodiesterase
39
What are CBP and p300?
Two related transcription co-activators
40
Apart from the transcription factor binding domains, what other domais are in CBP and p300?
HAT BR PHD
41
What is the function of the HAT domain?
Causes histone acetylation which is required for transcriptional regulation
42
What is the function of PHD?
Chromatin binding
43
What is the CREB binding domain?
KIX
44
What domain of CREB binds to KIX?
KID domain
45
What does the unphosphorylated form of CREB KID have?
A disordered domain
46
What is the function of phosphorylating CREB on Ser133?
Stabilises the structure
47
Once CBP or p300 are recruited to CREB, what do they do?
Acetylate histones to increase transcription
48
Apart from PKA, what other kinases can phosphorylate CREB on S133?
CaMK | MSK1/2
49
Despite MSK1/2 phosphorylating S133 on CREB, what does it not do?
Recruit CBP and p300
50
What are CRTCs?
Alternative CREB co-activators
51
What are the 3 isoforms of CRTCs?
1 2 3
52
Does CRTCs have catalytic activity?
no
53
How does CRTCs bind to CREB?
The N-terminal of CRTC binds to the bZIP domain of CREB
54
Can CRTCs bind to CREB when phosphorylation on S133 has not occured?
yes
55
What are the possible functions of CRTCs?
To stabilise the interaction between CREB and CBP or between CREB and components of the RNA polymerase complex
56
In unstimulated cells, where are CRTCs localised to?
The cytoplasm
57
How is CRTCs bound to 14-3-3 ?
By phosphorylation on 3 sites
58
What does 14-3-3 binding to CRTCs do?
Masks a nuclear localisation sequence and therefore CRTCs stay in the cytoplasm
59
What does dephosphorylation of CRTCs induce?
CRTCs translocate to the nucleus where it can bind to CRE
60
What promotes CRTCs dephosphorylation?
cAMP-PKA stimulation
61
What is SIK?
Salt inducible kinase
62
What are the 3 isoforms of SIK?
1, 2 and 3
63
When are SIK activated?
When they are phosphorylated by LKB1
64
What is the function of SIKs?
They phosphorylate CRTCs on the sites required for 14-3-3 binding
65
How is SIKs function inhibited?
By PKA phosphorylating it
66
What is the evidence against MAPK being able to stimulate CREB dependent transcription?
MAPK activation does not drive the transcription of classical CREB dependent luciferase reporter genes MAPK activation does not promote p300 and CBP recruitment Mutations in p300 and CBP do not effect MAPK induced transcription MAPK activation does not promote nucleur localisation of CRTCs Many CREB dependent genes also contain serum response elements in their promoters which could explain the regulation by MAPKs CREB may play a basal role in transcription - even if MAPK activation did induce CREB target genes in CREB KO this could be due to a basal and not a stimulated role for CREB
67
What is the evidence for MAPK stimulating CREB dependent transcription?
Many IEs induced by MAPKs are CREB targets There is some overlap between PKA-induced and MAPK-induced CREB target genes but there is also some differences Knockdown of CREB can reduce gene induction downstream of MAPK Deletion or inhibition of MSK1/2 reduced the induction of several IE genes downstream of stimuli which activate MAPK
68
As well as CREB, what else can MSK1/2 phosphorylate?
Histone H3 | Trim28
69
Since histone H3 can be phosphorylated by MSK1/2, what does this mean in terms of CREB?
MSK1/2 can induce IE genes independently of CREB
70
What happens if you KO Ser133 in CREB in mice?
They die shortly after birth
71
What happens if you change the Ser to Ala in Ser133 in CREB in mice?
They are viable and fertile but are born at less than the expected Mendelian frequency
72
What is required for the production of IL-10? How can you increase IL-10 expression
LPS | Increase it by adding PGE2 stimuli too

Advanced Cell Signalling (12 decks)

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