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MCD: Cancer > Signalling mechanisms of growth and division > Flashcards

Signalling mechanisms of growth and division Flashcards

1
Q

What happens to most adult cells in the absence of growth signals?

A

They go into G0, the quiescent phase.

Most adult cells are not constantly dividing.

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2
Q

What is c-Myc?

A

An oncogene, over expressed in many tumours.

A transcription factor, which stimulates the expression of cell cycle genes.

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3
Q

What are the key components of signalling pathways in the cell cycle?

A

Regulation of enzyme activity by protein phosphorylation (kinases)
Adaptor proteins
Regulation by GTP-binding proteins

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4
Q

How does the concentration of c-Myc change through the cell cycle?

A

Low in quiescent G0 phase.
If cell division is triggered (e.g. by adding a growth factor), there is a rapid increase in c-Myc (G1), then it plateaus at an intermediate level when the cell enters S phase.

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5
Q

How do growth factors stimulate signalling pathways?

A

Mitogenic growth factor binds to receptor protein tyrosine kinase.
It acts via small G (GTP-binding) protein (Ras).
This triggers a kinase cascade.
Immediate early genes (c-Jun, c-Fos, c-Myc- transcription factors) control the expression of other genes.

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6
Q

Give an example of a mitogenic growth factor.

A

Hepatocyte growth factor.

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7
Q

What is the role of the phosphorylated receptor protein tyrosine kinase (RPTK) in signalling?

A

RPTK recruits adaptor and signalling proteins, e.g. Grb2

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8
Q

What is the role of tyrosine phosphorylation in signalling?

A

Provides docking site for adaptor proteins.

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9
Q

What are protein domains and what is their role in signalling?

A

Functional and structural units that are copied in many proteins.
Important in molecular recognition- no enzymatic function of their own, but important in bringing other proteins together.

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10
Q

What is a modular adaptor protein?

A

There are different domains that are mixed and matched to give the protein different properties.

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11
Q

What are the 2 types of protein-protein interaction of Grb2?

A

SH2- binds to the phosphorylated tyrosines of the receptor.

SH3 (there are 2 copies)- bind to the proline rich regions of other proteins.

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12
Q

What are the 2 possible states of GTP binding proteins?

A

On- GTP bound

Off- GDP bound

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13
Q

What is Ras?

A

A GTP binding protein, very powerful molecular switch.

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14
Q

How are GTP binding proteins such as Ras activated?

A

Exchange factors, e.g. Sos, allow the GTP to replace GDP (exchange, not phosphorylation).
This is a self-regulating system.

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15
Q

What can hydrolysis of GTP to GDP be stimulated by?

A

GTPase activating proteins (GAPs)

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16
Q

What is the cycle of GTP binding proteins almost always controlled by in signalling?

A 
Exchange factors (e.g. Sos) that turn it on.
GTPase activating proteins (GAPs) that turn it off.
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17
Q

What is the main G-protein of growth factor stimulatory pathways?

A

Ras

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18
Q

What happens to Ras in cancer?

A

Ras protein is mutated in ways that cause it to be in the GTP bound form constantly- signalling activity is not turned off, so uncontrolled division may occur.
Ras can be oncologically activated by mutations that increase the amount of active GTP-loaded Ras.

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19
Q

What are the 2 main Ras mutations found in cancer?

A

V12Ras- prevents GAP binding (prevents inactivation)
L61Ras- prevents GTP hydrolysis
Both constitutively active.

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20
Q

What is the role of Ras in signalling?

A

Activates a protein kinase cascade.

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21
Q

What is the ERK cascade?

A

Extracellular signal-regulated kinase cascade.

Involved in the growth stimulatory signalling.

22
Q

What are the three kinases specific to ERK cascade?

A

Raf
MEK
ERK

23
Q

What is B-Raf?

A

Oncogene- mutationally activated in melanomas.

24
Q

What is the end result of protein kinase cascades in signalling?

A

Stimulates changes in cell protein activity and in gene expression to promote division.

25
Q

What does activating the growth factor pathway through the kinase cascade lead to?

A

Activation of a gene regulatory protein, which stimulates c-Myc production.

26
Q

What is cell cycle control based on?

A

Cyclically activated protein kinases.

27
Q

Where are cyclin-dependent kinases (Cdks) present?

A

In proliferating cells throughout the cell cycle.

28
Q

What is Cdk activity regulated by?

A

Interaction with cyclins

Phosphorylation

29
Q

How are Cdks activated?

A

By binding to cyclins.

30
Q

What are cyclins?

A

Activating proteins that are transiently expressed at specific point in the cell cycle. Once they have activated Cdks, cyclins are degraded. They are regulated at the level of expression.

31
Q

What do activated Cdks do?

A

Phosphorylate proteins on serine or threonine to drive cell cycle progression.

32
Q

What is mitosis promoting factor (MPF) made up of?

A

Cdk1 + Mitotic Cyclin B

33
Q

What activated the Cdk-cyclin complex?

A

Also regulated by phosphorylation.
CAK (Cdk activating kinase) puts and activating phosphorylation onto Cdk1.
Wee1 puts an inhibitory phosphorylation onto Cdk1.
Cdc25 takes off the inhibitory phosphate that was put on by Wee1.
MPF is then active.

34
Q

What activates Cdk1 at the end of interphase?

A

Dephosphorylation of the inhibitory site of Cdk1 by Cdc25. Active MPF is able to phosphorylate Cdc25 to increase its activity. This is a form of positive feedback that drives mitosis.

35
Q

What does the signal from fully attached kinetochores cause?

A

Cyclin B to be degraded
Cdk1 inactivated
Key substrates dephosphorylated
Mitosis progresses

36
Q

What does MPF do when active at the end of metaphase?

A

Phosphorylates a number of key substrates involved in the mitotic process.
This puts mitosis on hold when the substrates are phosphorylated.

37
Q

Which cyclin and Cdk control G1/S phase of mitosis?

A

Cdk2

Cyclin E

38
Q

Which cyclin and Cdk control S phase of mitosis?

A

Cdk2

Cyclin A

39
Q

What is the role of cyclins in the cell cycle?

A

Activate Cdks

Alter substrate specificity- substrate accessibility changes through cell cycle.

40
Q

What is the role of cyclin D in the cell cycle?

A

Activates Cdk4 and Cdk6 to stimulate synthesis of cyclin E. This triggers the cell cycle.

41
Q

How is gene expression regulated by Rb (retinoblastoma protein)?

A

pRb acts as a ‘brake’ on the cell cycle.
Cdks phosphorylate (at multiple sites) and progressively inactivate pRb- E2F transcription factors released.
Rb is a tumour suppressor.

42
Q

What proto-oncogenes are regulated by E2F transcription factors?

A

c-Myc
N-Myc
B-Myb
IGF-1

43
Q

What cell cycle genes are regulated by E2F transcription factors?

A 
E2F-1,2,3
pRb
p107
cyclin A
cyclin E
CDK4
CDK2
44
Q

What DNA synthesis genes are regulated by E2F transcription factors?

A

Thymidine kinase
Thymidine synthetase
Dihydrofolate reductase (DHFR)
DNA polymerase

45
Q

What does the initial release of E2F from pRb after phosphorylation allow?

A

Transcription of cyclin E.

Cyclin E then forms a complex with Cdk2.

46
Q

What are the 2 families of Cdk inhibitors (CKIs)?

A

INK4 family

CIP/KIP family

47
Q

How do INK4 CKIs have their effect?

A

G1 phase CKIs

Inhibit Cdk4/6 by displacing cyclin D.

48
Q

How do CIP/KIP CKIs have their effect?

A

S phase CKIs

Inhibit all Cdks by binding to the Cdk/cyclin complex.

49
Q

What is the role of CKIs in the cell cycle?

A

Add another level of regulation.

Must be degraded for the cell cycle to progress.

50
Q

What is the most important protein phosphorylated by start kinase?

A

Retinoblastoma.

51
Q

What is start kinase?

A

A complex of Cdk2 and G1 cyclin (e.g. cyclin E)- this phosphorylates substrates needed for G1/S phase.

52
Q

What is MPF?

A

M-phase promoting factor.

Phosphorylates proteins involved in mitosis, e.g. nuclear lamins (cause breakdown of nuclear envelope).

MCD: Cancer (17 decks)

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