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CMB2001 > CMB2001/L06 Transcriptional Responses to Stress & Infection II > Flashcards

CMB2001/L06 Transcriptional Responses to Stress & Infection II Flashcards

1
Q

What is the role of E3 Ubiquitin ligase?

A

Facilitates the attachment of ubiquitin chains to target proteins

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2
Q

Define hypoxia.

A

Lowering of the oxygen concentrations compared to sea level +-20.9% oxygen

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3
Q

Give 3 physiological processes that require a hypoxia response.

A

Placenta development
Heart
Bone
Vasculature development

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4
Q

What does hypoxia response allow adaptation to? (2)

A

High altitude living
Intense muscle exercise

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5
Q

Give 3 cellular responses to hypoxia.

A

Restoration of oxygen homeostasis
Cell survival
Cell death

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6
Q

What is the HIF system?

A

Hypoxia Inducible Factor
Heterodimeric transcription factor HIF-a and HIF-1B

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7
Q

Where is HIF-1a expressed?

A

Ubiquitously in all tissues

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8
Q

Where is HIF-2a expressed?

A

Restricted to certain tissues

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9
Q

Where is HIF-3a expressed?

A

Restricted to certain tissues
Lacks C-terminus transactivation domain

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10
Q

How does HIF-3a function?

A

As a dominant negative inhibitor for HIF-1a and HIF-2a
Has been shown to activate a different set of genes in hypoxia

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11
Q

What do Proline Hydroxylases (PHDs) require to function?

A

Oxygen

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12
Q

How is HIF-1a regulated?

A

Transcription
Translation - evades block
Post-translational regulation - lack of oxygen inactivates PHD proteins

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13
Q

Describe canonical regulation of HIF (in normoxia).

A

Oxygen sensing
Ubiquitination and degradation
Stabilisation in hypoxia
Dimerisation with HIF-1B
Transcriptional activation
Target genes

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14
Q

In what form can asparagine interact with target gene mRNA?

A

Unhydroxylated

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15
Q

Name 3 pathways controlled by HIF.

A

Oxygen supply
Transcription
Cellular metabolism
Cell growth
HIF control
Cell death

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16
Q

How does hypoxia aid cancer? (3)

A

Activation of HIF stimulates angiogenesis to bring oxygen and nutrients to tumour
Regulates other tumour characteristics: evasion and metastasis
Enhanced growth and survival and increased glycolysis

17
Q
A
18
Q

Describe the structure of p53.

A

Typical for transcription factors
Distinct DNA binding and multimerisation domains
Transactivation domain (TAD)
P - proline-rich domain
NLS- nuclear localisation sequence
Tet - tetramerisation domain

19
Q

Give 3 positive roles of p53.

A

Tumour suppression
Stem cell modulation
Development
Fertility

20
Q

Give 3 unfavourable roles of p53.

A

Ischemia
Treacher Collins syndrome
Neurodegeneration
Aging

21
Q

What is the role of ARF?

A

p14^ARF - tumour suppressor
Disrupts interaction between p53 and Mdm2
Increases levels of transcriptionally active p53

22
Q

When is p14^ARF expression induced?

A

As a result of increased cellular proliferation

23
Q

What is the role of Mdm2? (3)

A

E3 ubiquitin ligase
Promote ubiquitination of p53 for degradation by proteasome
Keeps p53 levels low in undamaged cells

24
Q

Describe how Mdm2 inhibits p53.

A

DNA damage causes phosphorylation of p53 at Ser15 by ARM or ATR kinases
Mdm2 phosphorylated
Disrupts interaction between p53 and Mdm2

25
Q

Describe the Mdm2 feedback loop.

A

p53 stimulates Mdm2 expression
Negative feedback loop limiting extent of p53 activation

26
Q

Give an example of negative feedback among transcription factor pathways.

A

p53 induces its inhibitor Mdm2 causing its proteolytic degradation
HIF1a induces PHD proteins that cause its proteolytic degradation
NF-kB induces its inhibitor IkBa that removes it from nucleus and retains it in cytoplasm

27
Q

Explain how cancer cells inhibit p53.

A

Mutation causes loss of ARF/ATM function
Mdm2 amplification
Viral infection of E6
Mutation or defects with p53
Arrests apoptosis

28
Q

What is Li-Fraumeni Syndrome?

A

Hereditary cancer disposition syndrome
Most commonly caused by mutation in gene TP53 for p53

29
Q

How do the NF-kB and HIF pathways differ?

A

NF-kB activation involves degradation of an inhibitor (IkBa)
HIF and p53 are degraded continuously in unstimulated cells and become stabilised upon exposure to activating stimulus

CMB2001 (11 decks)

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