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OV cancer > Signalling Mechanisms in Growth and Division > Flashcards

Signalling Mechanisms in Growth and Division Flashcards

1
Q

What transcription factor is stimulated by growth factor signalling and is vital to starting the cell cycle?

A

c-Myc

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2
Q

Give an example of an anti-cancer drug that targets tyrosine kinase receptors.

A

Herceptin – inhibits the Her2 tyrosine kinase receptor (important in many tumours e.g. breast)

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3
Q

Broadly speaking, how might Ras signalling be different in cancer?

A

Ras could be permanently switched on (in the GTP bound form), thus it constantly signals cell division

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4
Q

What is the family that the ERK cascade belongs to called?

A

MAPK cascade (Mitogen-activated protein kinase cascade)

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5
Q

What are the three kinases involved in the ERK cascade?

A

Raf
MEK
ERK

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6
Q

What important gene is turned on by the kinase cascade?

A

c-Myc

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7
Q

What type of kinase are cyclin-dependent kinases (Cdks)?

A

Serine-threonine kinases

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8
Q

What conditions do Cdks require to become activated?

A

Binding to cyclin

Phosphorylation (activating phosphorylation and removal of inhibitory phosphorylation)

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9
Q

What does the mitosis-promoting factor (MPF) consist of?

A

Cdk1 + cyclin B

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10
Q

What are the requirements, in terms of phosphorylation, for MPF to become active?

A

Cdk activating kinase (CAK) adds an activating phosphate and Wee1 adds an inhibitory phosphate at the same time
Cdc25 then removes the inhibitory phosphate

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11
Q

What activates MPF at the end of interphase?

A

Removal of the inhibitory phosphorylation by Cdc25

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12
Q

Describe the positive feedback loop that is formed by MPF activation.

A

Removal of the inhibitory phosphorylation by Cdc25 produces active MPF, which then phosphorylates Cdc25 and increases its activity meaning that more MPF can be activated

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13
Q

Which Cdk/cyclin is required for G1/S phase?

A

Cdk2-cyclin E

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14
Q

Which Cdk/cyclin is required for S phase?

A

Cdk2-cyclin A

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15
Q

How can the same Cdk be used for two different stages?

A

Cyclin binding alters the substrate specificity of Cdk

Also, different substrates are available at different stages of the cell cycle

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16
Q

What is one of the most important transcription targets of c-Myc?

A

Cyclin D

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17
Q

What is the first Cdk/cyclin complex that is formed when a cell goes from G0 to G1?

A

Cdk4/6-cyclin D

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18
Q

This Cdk/cyclin complex then stimulates the expression of the next cyclin in the cell cycle. What properties does this system give to the cell cycle?

A

This gives the cell cycle direction and timing (because the Cdk-cyclin complexes must reach a certain concentration before they can trigger the next stage of the cycle)

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19
Q

Give an example of a phosphorylation target of MPF that allows the cell cycle to progress.

A

Phosphorylation of nuclear lamins allows breakdown of the nuclear envelope

20
Q

What is start kinase and what is one of its most important targets?

A

Start kinase = Cdk2-cyclin E

Retinoblastoma

21
Q

Describe the role of retinoblastoma in the quiescent G0 state.

A

Retinoblastoma is unphosphorylated and binds to and sequesters a group of transcription factors called E2F

22
Q

Role of Cdk4/6-D

A

It multiply phosphorylates retinoblastoma – as it becomes phosphorylated it loses its affinity for E2F and releases E2F
This means that the E2F transcription factors can regulate gene expression and promote progression of the cell cycle

23
Q

What is one of the main targets of E2F?

A

Cyclin E

24
Q

What type of gene is retinoblastoma?

A

Tumour suppressor gene (it acts a break on the cell cycle)

25
Q

The initial release of E2F allows transcription of cyclin E leading to the formation of Cdk2-cyclin E. What effect does this complex have on retinoblastoma?

A

Cdk2-cyclin E further phosphorylates retinoblastoma so more E2F is released and the concentration of E2F increases

26
Q

What is the significance of the increasing concentration of E2F in terms of interphase?

A

This means that E2F can now bind to targets with a lower affinity (e.g. cyclin A gene promoter isn’t activated until the E2F concentration is high enough)

27
Q

What are the two families of Cdk inhibitors?

A

NK4

CIP/KIP

28
Q

During which phase do each of the NK4 and CIP/KIP act and how do they inhibit Cdk?

A

INK4 – G1 phase – it displaces cyclin D from the Cdk4/6-cyclin D complex
CIP/KIP – S phase – it binds to the Cdk/cyclin complexes and inhibits them
NOTE: these inhibitors need to be degraded at various stages for the cell cycle to progress

29
Q

State some common and important oncogenes.

A 
EGFR/HER2  
Ras 
Cyclin D1  
B-Raf 
c-Myc
30
Q

State some important tumour suppressor genes.

A

Rb – inactivated in many cancers

p27KIP1–under-expression correlates with poor prognosis in many malignancies

31
Q

When are Cdks present

A

Present throughout cell cycle in proliferating cells to control the cycle

32
Q

Life of cyclins

A

Transiently expressed
Levels regulated by levels of expression
Are quickly synthesised then degraded

33
Q

What happens when growth factor binds to GFR and where does ligand normally come from

A

Dimerisation with another ligand bound receptor- this allows trans-autophosphorylation of the others tyrosine residue

34
Q

What type of receptor is GFR

A

Tyrosine kinsae

35
Q

What does phosphorylation of tyrosine residue of GFR allow

A

Docking of Grb2 protein via its SH2 region

36
Q

Describe structure of Grb2 protein

A

Two SH3 regions surrounding central SH2

37
Q

What does SH3 region of Grb2 bind to

A

Proline rich region of SOS

38
Q

What does SOS do

A

It is an exchange factor- exchanges GDP on RAS for GTP thus activating it

39
Q

How is activated RAS deactivated

A

GTPase activating protein

40
Q

Role of Ras

A

To phosphorylate Raf

41
Q

Where are Ras and Raf found

A

They are membrane bound

42
Q

Phopsphorylating chain

A

Ras
Raf
MEK
ERK

43
Q

What do Raf and Mek use to phosphorylate their next protein

A

ATP

44
Q

What happens to ERK after it is phosphorylated

A

Goes to nucleus and phosphorylates C-Myc protein

45
Q

Order of cdks in cell cycle

A

4/6
2
2
1

46
Q

Order of cyclins in cell cycle

A

D
E
A
B

OV cancer (15 decks)

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