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BI3352: Cancer - Cellular and Molecular Mechanisms and Therapies > Growth Autonomy 3 > Flashcards

Growth Autonomy 3 Flashcards

1
Q

Activity of which molecule allows for the phosphorylation of PIP2 into PIP3?

1 mark

A

Classes 1A and 1B of PI3K

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2
Q

What phoshporylates PIP2 into PIP3?

1 mark

A

PI3K in classes 1,2 and 3

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3
Q

What is class 1a and 1b PI3K activated by?

2 marks

A

Class 1A: receptor tyrosine kinases

Class 1B: G-protein coupled receptors

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4
Q

What is the difference between the class sizes of PI3K?

1 mark

A

Regulatory subunit size

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5
Q

What does the regulatory subunit of PI3K’s do?
2 marks

A
  • Inhibits and represses kinase activty in the catalytic subunit
  • When bound to activated receptor changes its hold on shape interacting with catalytic subunit and relieving repression
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6
Q

What do lipid kinases phosphorylate?

1 mark

A

Lipid molecules

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7
Q

Give an overview of the PI3K/Akt/mTOR pathway.

5 marks

A
  1. PI3K phoshporylates lipid molecule on 3 position - get PIP3 recognized by Akt
  2. Ph domain recognise lipid molecule (Akt not activated but brought to correct localisation in cells so can be phoshporylated by PDK1 and PDK2 (second phoshporylation)
  3. Activated Akt disassociate from PIP3
  4. PTEN dephoshporylate PIP3 - takes phosphate from third position and goes back to PIP2 - shuts down signalling
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8
Q

What can cause abberant Akt signalling?

4 matks

A
  • Overstimulation upstream oncogenic events
  • Loss of negative regulation e.g. PTEN
  • Activating mutations in PI3K
  • Activating mutations in Akt
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9
Q

Where do mutations often occur in PTEN?

2 marks

A
  • Phosphatase domain - reducing or inhibiting ability to work as lipid phosphatase
  • PDZ domain - PTEN is unable to anchor to membrane properly. Not in correct position can’t act on anti-phosphorylate PIP3
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10
Q

Where in the body are PTEN mutations mostly found?
1 mark

A

Brain

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11
Q

What is deregulated Akt activity associated with?

1 mark

A

Increased cell proliferation and advanced tumor stage

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12
Q

How does Akt function in the cell cycle?

2 marks

A
  • Prevents expression of cdk inhibitors p21 and p27
  • Can also phosphorylate proteins
  • (Look at slide 7)
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13
Q

What members make up the Akt family?

3 marks

A

Akt1, Akt2, Akt3 - serine threonine kinases

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14
Q

What is the purpose of Akt1?

2 marks

A
  • Involved in cell growth and survival - drives cell cycle and inhibits apoptosis
  • Most ubiquitously expressed in cell in cellular processes
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15
Q

What is the role of Akt2?

1 mark

A

In insulin signalling - needed to induce glucose transport

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16
Q

What is the role of Akt3?

A

No defined role - but predominantly expressed in the brain

17
Q

What are the key residues phosphorylated during the activation of Akt?

2 marks

A

Thr 308 (by PDK1 for partial activation)

Ser 473 (via mTORC2 for full activation)

18
Q

What are some of the driver mutations in Akt?

3 marks

A

E17K, L52R and Q79K

19
Q

What does E17K do?

3 marks

A
  • Enhanve ability of Akt to bind to PIP3
  • Found in PH domain
  • Don’t confer sensitivity or resistance to Akt inhibitors
20
Q

Where are the most common mutations in PI3K found?

A

Class 1A

21
Q

Why is PI3K hyperactiated in 1/3 human colon carcinomas?

2 marks

A

Because of mutations affecting its p110a catalytic subunit.

Mutations make the PIK3CA gene which encodes alpha isoform of PI3K – the second most mutated oncogene in human cancers

22
Q

Where does key signalling in Class 1A subunits occur?

1 mark

A

In catalytic units p110a * and p110b. Expression of p110d

23
Q

Which gene encodes for p110a catalytic unit?

1 mark

A

PIK3CA gene

24
Q

How does mutated PI3KCA affect Akt activity?

1 mark

A

Increases it

25
Q

What mutations often occur in PI3KCA and where?

2 marks

A
  • Missense mutations
  • Helical and kinase domains - causing constitutively active catalytic p110a subunit
26
Q

What do the graphs show?

3 marks

A
  • N drug at top designed to specifically target alpha subunit of p110a
  • Can see dosage point that affects animals hypoglycaemic levels
  • So able to get an effective dose of drug without destroying animals hypoglycemic levels
  • Can see that tumour growth is significantly reduced
27
Q

What does mTOR stand for and what is it?

2 marks

A
  • Mammalian target of rapamycin
  • Serine threonine kinase exists as two different complexes
  • mTOR master regulator in cell
28
Q

Give an overvie of the PTEN-PI3K-AKT-mTOR pathway.

A
  • Activated pi3k converting pip2 to 3 facilitating activation of akt
  • Pdk1 phosphorylating and helping activate akt other phosphorylation occurring by torc2 – now akt active
  • Akt will affect p27 and p21
  • and will phosphorylate and inactivate gsk allowing cyclin d to accumulate in g1 phase
  • Akt phosphorylates and inactivates BAD which inhibits apopotiosis inactivates fox0 so al fox0 genes not transcribed another target for akt is torc2 complex
  • Torc2 involved in actiating akt and torc1 is downstream target for akt
  • Need to get protein synthesis going to make new components for daughter cells
29
Q

Why is mTOR a rational therapeutic target?

3 marks

A

Can inhibit rapamycin - more developed and effective drugs target it now aka rapalogs (derivatives of rapamycin)

Rapalogs in pre-clinical studies showed if regulated AKT because tumour cells lost PTEN actiivty. Appeared to sensitise cells to treat e t with rapalogs

30
Q

What can be seen in PTEN absent cells in presence of rapamycin logo?

A
  • Increase i tumour inhibitory growth
31
Q

Does a lack of PTEN mean constant response to mTOR inhibition?

A

Does not always mean will have enhanced response to mTOR inhibition

32
Q

What is unexpected of mTORC1 showing better efficacy than mTORC2?

A

Unexpected because torc2 has a direct affect on akt whereas mtorc all the way down

33
Q

ACTIVE RECALL ON SLIDE

A

BI3352: Cancer - Cellular and Molecular Mechanisms and Therapies (7 decks)

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