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Eukaryotic Gene Expression > L6 - Signal transduction of TFs > Flashcards

L6 - Signal transduction of TFs Flashcards

1
Q

How does cAMP transmit?

A

Responses to many hormones and neurotransmitters via GPCRs , Adenylate cyclase and PKA

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2
Q

What is the cascade of cAMP signalling?

A
  1. cAMP binds PKA and releases catalytic subunit
  2. PKA phosphor CREB
  3. CREB recuits HAT CBP (CREB binding protein)
  4. PKA also phosphorylates many other targets eg inhibits glycogen syn
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3
Q

What are the features of NF-kB?

A

Activated by all stimuli that elicit an immune response

Induce genes encoding many components of IS eg cytokines

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4
Q

How is p-65/-50 PTMd?

A

Unusual - sulphydration of a Cys residue

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5
Q

What can also stimulate DNA binding by p65-p50?

A

Ribosomal protein RPS3

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6
Q

What does IKK do?

A

Phosphorylates RPS3 so it translocates to nucleus to associate with p65/p50 (requires sulphydration of NF-kB)

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7
Q

What sequesters NF-kB proteins?

A

By IkB proteins with 6 ankyrin repeats

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8
Q

How do ankyrin repeats sequester NF-kB?

A

Make extensive contacts with rel homology region of NF-kB and mask nuclear localisation signal, causing cytoplasmic retention

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9
Q

How is the degregulation of NF-kB involved in cancer?

A

c-Rel gene amplified in B cell lymphomas

NF-kB2 can undergo translocation in lymphomas which truncate p100 precursor, releasing active p52

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10
Q

What is HTLV-1 and how does it spread?

A

Human T-cell leukemia virus

Transmitted through unprotected sec, contaminated blood transfusions and breastfeeding

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11
Q

What are the internal symptoms of HTLV-1?

A

Transformed T cells show constitutive nuclear activated NF-kB
Viral protein Tax binds proteasome and stimulates degradation IkB and stimulation of NF-kB1+2
Tax recrits CREB and CBP yo HTLV-1 promoter, stimulating txn

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12
Q

What other viruses also activate NF-kB?

A

HIV, HBV, EBV

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13
Q

What does mutation of IkB phosphoacceptor sites for IKK make?

A

A super repressor that is not degraded

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14
Q

What does the super repressor inhibit and what does this cause?

A

Twist, a bHLH TF required for limb development

Saethre-Chotzen syndrome (defects of hands, feet and cranium [fuse together])

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15
Q

What are STATs and how many are there?

A

Signal transducers and activators of transcription

7 in humans with unique functions

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16
Q

What are STATs’ function?

A
  • Exist in cytoplasm until activator by receptors for growth factors or cytokines
  • Ligand binding to receptors causes phosphor of receptor, creating docking site for STATs
  • JAKS phosphorylate STATs and they dimerise and enter nucleus to activate txn
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17
Q

What do gene products of STATs promote?

A

Cell survival (survivin)
Proliferation (cyclin and c-Myc)
Angiogenesis (VEGF)

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18
Q

What kinds of mutations involving STATs can cause cancer?

A

Silencing of Tyr phosphatases that reverse STAT activation
Mutations in JAKs cause constitutive action of STAT3
Mut in STAT3 can promote dimerization

19
Q

What is the positive feedback loop of STATs?

A

Gene product of STATs can be HIF-1
HIF-1 induces gene for pyruvate kinase M2 (PKM2)
PM2 phosphor STAT3 triggering dimerization and action
Positive feedback driving tumourigenesis

20
Q

What does PKM2 do and how is this involved in cancer?

A

Catalyses penultimate step of glycolysis - Watburg effect (cancer cells use aerobic glycolysis to consume glucose at high rate)

21
Q

What does STAT3 promote?

A

Migration of prostate cancer cells (activated in 67% of bone metastases)

22
Q

What is a treatment for STAT3 cancer and details>

A

LLL12 - binds to phosphor-Tyr docking site and induces apoptosis

23
Q

What are Wnts?

A

Small secreted proteins that bind serpentine receptor of Frizzled family at cell surface

24
Q

What is beta-catenin?

A

Txn coactivator that is degraded in absence of Wnt signals

25
Q

What happens when Wnt binds to Frizzled?

A

Stabilises beta-catenin which enters nucleus, binds T cell factor (TCF) and activates txn of genes eg cyclin D1 and c-Myc

26
Q

What is APC@>

A

Adenomatous polyposis coli

Tumour suppressor that binds b-catenin with GSK3 kinase

27
Q

What does GKS3 do to b-catenin?

A

Phosphorylates it, targeting it for ubiquitination and proteasomal degradation

28
Q

How is the action of GSK3 changed by Wnt signalling?

A

Blocks phos of b-catenin by GSK3 so can enter nucleus

29
Q

What occurs when APC mutated?

A

Release of B-catenin and causes colon cancers

30
Q

What are nuclear receptors used for and why?

A

Control gradual processes because they lack the speed of kinase cascades

31
Q

What do nuclear receptors typically look like?

A

Central DBD and C terminal ligand binding domain.

32
Q

What is PPARgamma and what is it involved in?

A

Perozisome proliferator activated receptor

Insulin resitance, diabetes, adipocyre differentiation

33
Q

What does GOF mutation in PPARgamma cause?

A

Promote adipocyte differentiation and obesity

34
Q

How does the oestrogen receptor (ER) activate txn?

A
  • oestrogen triggers conformation change in ER LBD, allowing dimerise and binding to ERE DNA
  • ER recirts coactivators
  • Acetylated histones attract BRD4 which recruits P-TEFb, which phosphorylates NELF, DSIF and pol2 CTD Ser2 allowing promoter clearance
35
Q

What is the structure of bromodomains?

A

Bundle of 4 a-helices joined by two variable loops forming an invaginated hydrophobic pocket for binding acetylated lysine (for reading histone markers)

36
Q

What are the BET subfamily?

A

Bromodomain and extraterminal

37
Q

How is BRD4 involved in cancer?

A

Chomrosomal translocations drive NUT-midline carcinomas

38
Q

What are the treatments for BRD4 involved cancers?

A

BET inhibitors (eg I-BET) selective for BET family and do not inhibit other bromodomains

39
Q

How is the ER involved in cancer?

A

ER expression feature of 70% of breast cancers

Gene encoding ER amplified in up to 20% of breast cancers

40
Q

Are ER breast cancers good or bad (relatively)?

A

ER+ breast cancers have bettr prognosis because of hormonal therapies

41
Q

What is a successful anti-oestrogen and how does it work?

A

Tamoxifen

Changes conformation of helix 12 (attracts coactivators) of oestrogen to attract co-represors

42
Q

What is AIB1?

A

Specialised nuclear HAT used by activators with oestrogen (amplified in 10% of breast cancers)

43
Q

What is a therapy for prostate cancer?

A

Anti-androgen that binds AR and prevents action

44
Q

What is CRPC and what is common in it?

A

Castration resitant prostate cancer

AR gene amplified in 58% of cases

Eukaryotic Gene Expression (8 decks)

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