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Eukaryotic Gene Expression > L4 - Regulation of TFs > Flashcards

L4 - Regulation of TFs Flashcards

1
Q

How is activity of TFs commonly regulated and whats an example of it?

A

Post-translational modifications )(PTMs)

p53 is heavily PTMs

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2
Q

What stimuli can cause TFs to be regulated?

A

Hypoxia
DNA damage
Telomere erosion
dNTP depletion

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3
Q

How can TFs be modified (7 ways)?

A 
Ubiquitination
Methylation
Neddylation
Sumolation
Glycosylation
Acetylation
Phosphorylation
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4
Q

What is Mdm2 and what is its function?

A

E3 ligase

Controls p53 level by ubiquitation

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5
Q

What do Mdm2 KO mice do?

A

Die in utero due to p53-induced apoptosis

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6
Q

What are nutlins?

A

Anti-cancer Drugs to occupy p-53 binding pocket of Mdm2 to prevent degradation

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7
Q

What is neddylation and sumoylation?

A

Addition of NEDD8 and SUMO

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8
Q

What do NEDD8 and SUMO do?

A

Influence p53’s ability to regulate txn depending on accepter site, target gene and cel ltype

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9
Q

What phosphorylates p53 and where?

A

ATM kinase on Ser15

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10
Q

Why is p53 phosphor?

A

In response to DNA damage - stabilises p53 by inhibiting interaction with Mdm2 - allows p53 to accumulate to direct apoptosis or cell cycle arrest until damage repaired

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11
Q

What acetylates p53 and why?

A

HATS eg p300 and CBP

Stimulates ability to activate some genes

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12
Q

What did mutating the eight lys residues that are acetylated in p53 do?

A

Retained DNA binding activity and ability to activate MDM2 but lost ability to induce p32 exp or cell cycle arrest

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13
Q

What is the use of negative feedback control?

A

Allows transient response that switches itself off once stimulus removed

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14
Q

What is the negative feedback of p53?

A

Gene encoding MDM2 is a target for p53 - prevents excessive accum of p53 and return to basal levels once stimuli removed

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15
Q

What happens when p53 is monoubiquitinated?

A

Exported from the nucleus

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16
Q

What favours polyubiquitination (go for degradation)?

A

Higher levels of MDM2

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17
Q

What is HSF and where is it found?

A

Heat shock factor

Sequestered with hsp90 in the cytoplasm

18
Q

What happens when cells are heat shocked?

A

Dissociated hsp90 chaperone from HSF so it can enter nucleus to activate txn

19
Q

What 2 things happen to HSF before it activates txn?

A

Phosphorylated and also trimerises

20
Q

What ae steroid receptors

A

TFs that require steroid ligands for activity

21
Q

What does steroid binding trigger?

A

hsp90 chaperone to dissociate and allows receptor to enter nucleus to effect txn

22
Q

What is NF-kB family involved in?

A

Immune response

23
Q

Where and how is IkB found, and how is this changed?

A

Sequested in cytoplasm with p50 and p65

IkB is phosphorylated and ubiquinated and degraded allowing p50 and p65 to go to nucelus

24
Q

What is the negative feedback for NF-kB?

A

Gene encoding IkB is a target for NF-kB (so the gene that p50 and p65 induce has IkB too so it comes and gets them again)

25
Q

What TF is regulated by dimerization?

A

MYC is unable to bind DNA without MAX

26
Q

Why do MYC and MAX have to dimerise?

A

Both have bHLH/leucine zipper domains that only function after dimerisaiton
HLHZip forms extended alpha-helical dimerization interface

27
Q

What is the difference between MYC and MAX?

A

MAX can homodimerise, MYC needs MAX

28
Q

What does MAD do?

A

Binds DNA with MAX to repress txn by recruiting HDACs

Expressed in differentiated cells

29
Q

What does MYC do to DNA?

A

Activates txn by recruiting HAts, P-TEFb, TBP, TFIIH

Expressed in proliferating cells

30
Q

What is MyoD and what are its features?

A

a TF that can induce myogenic differentiation
Has a bHLHZip
Dimerises with E2A for function

31
Q

What is E2A

A

bHLH protein essential for lymphocyte development

Also a putative tumour suppressor

32
Q

What are ID proteins and what are their features?

A

Respressors of bHLH proteins

Have HLH domain so can dimerise with E2A but lacks DNA binding domain (E2A/ID heterodimers inactive)

33
Q

What can IDs block other than E2A?

A

Block MyoD function by sequestering E2A

34
Q

Where are IDs common and uncommon?

A

Abundant in stem cells and proliferating cells but rare in differentiated cells

35
Q

How are ID proteins involved in cancers?

A

ID overexpression in mice causes fatal malignancies.

Elevated ID predicts poor prognosis

36
Q

What binds to and suppresses ID proteins and how was this shown?

A

RB (tumour suppressor)

Mice with 1 RB allele predisposed to pituitary tumours

37
Q

What decreased tumour incidence in RB- mice and what did this show?

A

ID2 gene deletion

Inhibition of ID2 is important for tumour suppression by RB

38
Q

What can ID2 do?

A

Promote angiogenesis by inducing VEGF

39
Q

What is HIF and what is its function?

A

Hypoxia inducible factor

Cells starved of oxygen use it to induce VEGF and other genes

40
Q

Features of HIF?

A

Only stable under hypoxic conditions (at normal O it is hydroxylated by prolyl hydroxylases (use o2 as co-substrate) then ubiquitinated)

41
Q

What is VHL?

A

E3 ubiquitin ligase that recognises hydroxylated proline residues on HIF and targets it for degradation

42
Q

What do mutation in VHL cause?

A

Active HIF under normoxic conditions so inappropriate angiogenesis
Von Hippel-Landau disease

Eukaryotic Gene Expression (8 decks)

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