3. Signalling mechanisms in growth and division Flashcards Preview

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Flashcards in 3. Signalling mechanisms in growth and division Deck (26)
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1
Q

What sort of enzymes are Cdks?

A

Serine-threonine kinases

2
Q

What things are required for Cdk activation?

A

Specific cyclin

Phosphorylation

3
Q

Summarise the life cycle of a cyclin

A

Expressed at apporpriate point in cell cycle

Once it has bound to a Cdk to activate it = degraded

4
Q

What is M-phase Promoting Factor made up of?

A

Cdk1-Cyclin B

5
Q

Recall the phosphorylation reactions involved in Cdk activation

A
  1. Phosphorylation by CAK

2. Removal of inhibitory phosphate by Wee1

6
Q

How is Wee1 phosphate removal activated?

A

CDC25 phosphatase

7
Q

Describe the positive feedback loop involved in Cdk control

A

CDC25P –> increased MPF –> drives increased CDC25P activation

8
Q

What is the function of MPF?

A

Phosphorylates nuclear lamins to initiate nuclear envelope breakdown

9
Q

How is MPF inactivated?

A

Kinetochore attachment to spindle releases signal to degrade cyclin B

10
Q

Describe the mechanisms controlling entry into G1 phase

A
  1. Mitogenic Growth Factor binds RPTK
  2. RPTK activates Ras
  3. Ras –> MAPK/ERK cascade
  4. MAPK/ERK cascade –> c-Myc expression
  5. Cdk4/6-Cyclin D complex required
11
Q

Recall the kinases specific to the MAPK/ERK pathway

A

Raf/MEK/ERK

12
Q

What is the role of Grb2?

A

Binds to TRPK to inactivate Ras

13
Q

Describe the control of Ras

A

Activated when bound to GTP, inactive when bound to GDP

  1. Exchange factor Sos activates to Ras-GTP
  2. GAP hydrolyses to Ras-GDP to inactivate
14
Q

What is the role of the Cdk4/6-Cyclin D complex?

A
  1. Activate start kinase (Cdk2-Cyclin E)

2. Phosphorylate retinoblastoma

15
Q

Recall the role and control of retinoblastoma protein (pRb)

A

Unphosphorylated in G0 as bound to E2F transcription factors in cytoplasm
When phosphorylated by SK, E2F released
E2F TFs bind to promoters on cell-cycle progression genes including cyclin E

16
Q

What sort of protein is retinoblastoma?

A

Tumour suppressor gene

17
Q

Recall 3 targets of E2F TFs

A
  1. Increase cyclin E expression, Cyclin A at higher concentrations
  2. Regulate proto-oncogenes eg Myc
  3. Control S phase proteins eg thymidine kinase
18
Q

Recall the feedback loop that E2F is involved in

A

E2F stimu;ates Cdk2-Cyclin E which in turn stimulates pRb: pRb causes more E2F to be released = positive feedback

19
Q

Recall the families of CKIs, their members and their function

A
  1. INK4 (P15/16/18/19) = displaces cyclin D from Cdk4/6

2. CIP/KIP (P21/27/57) = inhibits all Cdk-Cyclin complexes

20
Q

Which transcription factor is required for entry into the cell cycle?

A

c-Myc

21
Q

How do growth factors activate RPTKs? (3 steps)

A
  1. Monomeric GF brings 2 receptors togetehr to form active dimer
  2. 2 elements of dimer cross-phosphorylate tyrosine residues in the intracellular domain
  3. Adaptor proteins use phosphorylated tyrosine residues as docking sites
22
Q

How does Herceptin target the cell cycle?

A

Inhibits Her2 Receptor tyrosine kinase

23
Q

What is the key adaptor protein involved in cell cycle control?

A

Grb2

24
Q

Recall the sites of interaction of Grb2

A
  1. SH2 domain interactions = binds Grb to phosphorylated tyrosine resides of RPTKs
  2. SH3 domain interactions = binds Grb to proline-rich regions of Sos
25
Q

What does GAP stand for with relation to cell cycle control?

A

GTPase Activating Proteins

26
Q

Recall 2 common Ras mutations and their effect

A
  1. V12Ras = Gly–> Val at Pos 12: prevent GAP binding

2. L61Ras = Glu –> Leu at Pos 61: inhibits GAP so Ras is constantly bound to GTP