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Cancer Y2 > Signalling Mechanisms in Growth > Flashcards

Signalling Mechanisms in Growth Flashcards

1
Q

What is the quiescent phase?What organ cell is normally found in this?

A

G0, hepatic cells

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2
Q

Which proto-oncogene has a key role in the entry into the cell cycle

A

C-Myc

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3
Q

What is C-Myc

A

porto-oncogene that has a key role in the entry into the cell cycle

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4
Q

What is the concentration of C-Myc in G0

A

Low

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5
Q

When does the concentration of C-Myc rise rapidly

A

when cell division is triggered

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6
Q

What does C-Myc do

A

controls a lot of genes involved in the cell cycle progression

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7
Q

What are the key components of signalling pathways (3)

A
  1. Regulation of enzyme activity by protein phosphorylation (kinases)
  2. Adapter proteins
  3. Regulation by GTP-binding proteins – class of signalling molecules that are prevalent in many tumours.
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8
Q

what is a mitogenic GF? Example?

A

a growth factor that induces mitosis in a cell (e.g. hepatocyte growth factor)

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9
Q

Describe mitogenic GF stimulation of signalling pathways starting with a GF arriving and binding to its receptor

A

The growth factor arrives and binds to a receptor (usually tyrosine kinase type receptors)
It then acts via small GTP-binding protein (Ras)
This triggers a kinase cascade
This activates genes required for progression of the cell through the cell cycle- this is slower because it requires transcription and translation to take place
One of the genes triggered early in the kinase cascade is c-Myc

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10
Q

C-Myc is triggered by …

A

Growth factors activating RAS which triggers a kinase cascade trigger c-Myc

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11
Q

What is the end action of a phosphorylated receptor protein tyrosine kinase (RPTK)

A

Recruits adaptor and signalling protein

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12
Q

E.g. of an adaptor protein?

A

Grb2

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13
Q

Describe the process of phosphorylating a RPTK at a molecular level? Residues of what amino acid is phosphorylated?

A
  • The receptors normally sit on the plasma membrane as monomers but most growth factors are dimeric
  • When dimeric growth factor binds to two receptor tyrosine kinase molecules, it brings them closer together and their respective tyrosine kinase domains cross-phosphorylate one another
  • Tyrosine kinases use the gamma phosphate of ATP to phosphorylate tyrosine residues in proteins
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14
Q

What do the phosphorylated tyrosine domains of RPTK serve as

A

docking sites for ADAPTOR proteins

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15
Q

What serves as docking sites for ADAPTOR proteins

A

The phosphorylated tyrosine domains of RPTK

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16
Q

what genes are mutationally activated or overexpressed in many breast cancers

A

EGFR/HER2

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17
Q

EGFR/HER2 mutationally activation/ overexpression is indicative of what

A

Breast cancer

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18
Q

What antibody treatment for breast cancer is there?

A

Anti-her2 receptor tyrosine kinase antibodies

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19
Q

What is Ras

A

Small GTP binding protein

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20
Q

Grb2 is an…

A

Adaptor protein

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21
Q

Domains of Grb2?

A

1 SH2 domain and 2 SH3

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22
Q

What does an SH2 domain bind to

A

phosphorylated tyrosine

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23
Q

What domain on a Grb2 binds to phosphorylated tyrosine

A

SH2

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24
Q

What does an SH3 domain bind to

A

Proline rich regions

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25
Q

What domain on a Grb2 binds to Proline rich regions

A

SH3

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26
Q

e.g. of a Small GTP binding protein

A

Ras

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27
Q

What is the on form of ras

A

GTP bound

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28
Q

What is the off form of ras

A

GDP bound

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29
Q

What does Sos catalyse

A

the exchange of GDP for GTP on Ras

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30
Q

the exchange of GDP for GTP on Ras is catalysed by what

A

Sos

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31
Q

How is Ras self-regulated

A

is self-regulated, it can hydrolyse GTP to GDP to turn itself off
- intrinsic GTP hydrolysis capability

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32
Q

What stimulates hydrolysis of the GTP on Ras

A
  • intrinsic GTP hydrolysis capability and

GTPase activating proteins (GAPs)

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33
Q

What turns ras on

A

Sos

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34
Q

What turns ras off

A

itself and GTPase activating proteins (GAPs)

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35
Q

What can mutations of Ras cause and how

A

Cancer, mutated to be constantly on and GTP bound as Ras is the main GTP binding protein in GF stimulatory pathways

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36
Q

Which domains on Grb2 bind to the RPTK and which to Sos

A

SH2 to RPTK and SH3 to Sos

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37
Q

Where can you find Sos

A

bound to Grb2 (adaptor protein)

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38
Q

Describe RPTK signalling to Ras starting with phosphorylation of the receptor

A
  • When the RPTK becomes activated you get phosphorylation of the receptor
  • Then Grb2 binds to the phosphorylated tyrosine domains, bringing Sos close enough to the membrane to activate Ras
  • Sos allows the exchange of GDP for GTP in Ras This changes the conformation of Ras, making it into an activate state that can signal downstream and can allow propagation the signal
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39
Q

What does Ras need to bind to to signal downstream

A

The plasma membrane

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40
Q

2 forms of ONCOGENICALLY ACTIVATE Ras?

A

V12Ras

L61Ras

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41
Q

How is V12 Ras oncogenic

A

prevents GAPs from binding to Ras, meaning Ras can’t turn off easily

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42
Q

How is L61 Ras oncogenic

A

mutation inhibits the intrinsic GTPase activity of the Ras protein preventing GTP hydrolysis

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43
Q

Which form of Ras does this describe: mutation inhibits the intrinsic GTPase activity of the Ras protein preventing GTP hydrolysis

A

L61 Ras

44
Q

Which form of Ras does this describe: prevents GAPs from binding to Ras, meaning Ras can’t turn off easily

A

V12 Ras

45
Q

What does GTP bound Ras do

A
  • GTP-bound Ras binds to a kinase and activates it and that kinase activates several other kinases
  • The kinase cascade involved in the growth stimulatory signalling is called the ERK cascade (extracellular signal-regulated kinase cascade)
  • This type of kinase cascade is also known as a MAPK cascade (mitogen-activated protein kinase cascade)
46
Q

What starts the ERK cascade (extracellular signal-regulated kinase cascade)

A
  • GTP-bound Ras binds to a kinase and activates it and that kinase activates several other kinases
47
Q

What starts the MAPK cascade (mitogen-activated protein kinase cascade)

A
  • GTP-bound Ras binds to a kinase and activates it and that kinase activates several other kinases
48
Q

In the ERK/MAPK cascade, what is the first kinase activated by and what is it called

A

First kinase activated by Ras is called Raf or MAPKKK

49
Q

In the ERK/MAPK cascade, what is the second kinase activated by and what is it called

A

Activated by Raf or MAPKKK

Second is MEK or MAPKK

50
Q

In the ERK/MAPK cascade, what is the third (final) kinase activated by and what is it called

A

Activated by MEK or MAPKK.

The final one is ERK or MAPK

51
Q

What does the ERK/MAPK cascade achieve

A

Phosphorylates a number of proteins and changes their activity

52
Q

What is the key group proteins ERK/MAPK cascade phosphorylates

A

gene regulatory proteins (transcription factors)

53
Q

What do gene regulatory proteins (transcription factors) do once phosphorylated

A

regulate gene expression

54
Q

What phosphorylates gene regulatory proteins (transcription factors)

A

ERK/MAPK cascade

55
Q

one of the most important genes activates by the ERK/MAPK cascade

A

c-Myc

56
Q

What are Myc and Ras genes examples of

A

ONCOGENES

57
Q

What’re Cyclin-dependent kinases (Cdks)?

A

serine-threonine dependant kinases

58
Q

what do cyclins do

A

Activate cdks

59
Q

What happens to the cyclin once a cdk is activated? what is this a form of

A

it degrades, form of regulation

60
Q

when do cyclin levels rise

A

become expressed during mitosis and then go away (degraded), and then come up again in the next mitosis

61
Q

What activates Cyclin-dependent kinases (Cdks)?

A

Cyclin

62
Q

explain the variety of cyclins

A
  • There are different cyclin-Cdk complexes that trigger different events in the cell cycle
63
Q

What is cyclin that promotes mitosis

A

mitotic cyclin

64
Q

What is cyclin that promotes DNA replication

A

S phase cyclin

65
Q

what is the m-phase promoting factor

A

controls the progression through mitosis- the Cdk is being activated by a mitotic cyclin

66
Q

Cdk is being activated by a mitotic cyclin is called …

A

m-phase promoting factor

67
Q

What is an example of an activated CDK

A

m-phase promoting factor, MPF

or start kinase

68
Q

What does an activated M phase promoting factor do

A
  • MPF phosphorylates proteins involved in mitosis e.g. nuclear lamins (cause breakdown of the nuclear envelope)
69
Q

What do nuclear lamins do

A
  • Breakdown of the nuclear envelope is caused by phosphorylation of nuclear lamins
70
Q

What does an M phase promoting factor consist of

A

Cdk1 and mitotic cyclin

71
Q

What does Cdk1 and mitotic cyclin form

A

MPK

72
Q

What forms start kinase

A

Cdk2 and an G1 cyclin (e.g. cyclin E)

73
Q

What does start kinase do, what’s its most important function

A

phosphorylates substrates needed for that phase, most important protein that is phosphorylated by start kinase is RETINOBLASTOMA

74
Q

is a Cdk cyclin complex fully active?

A

No

75
Q

What happens to make a Cdk cyclin complex become fully active (3)

A

phosphorylation by Cdk activating kinase
inhibitory phosphorylation by Wee 1
removal of the inhibition by Cdc25

76
Q

What puts an activating phosphorylation of Cdk1

A

CAK puts an activating phosphorylation on Cdk1

77
Q

What puts an inhibitory phosphorylation of Cdk1

A

Wee1

78
Q

What takes off the inhibitory phosphorylation of Cdk1

A

Cdc25

79
Q

What does CAK do

A

puts an activating phosphorylation on Cdk1

80
Q

What does Cdc25 do

A

Takes off the inhibitory phosphorylation of Cdk1

81
Q

What does Wee1 do

A

puts an inhibitory phosphorylation of Cdk1

82
Q

When is Cdk1 dephosphorylated. to activate it

A

end of interphase

83
Q

What positive feedback effect does MPF have

A
  • Active MPF is able to phosphorylate Cdc25 to increase its activity
  • This is a form of positive feedback that drives mitosis
  • As soon as you get some active Cdk1 then you activate more Cdc25, which in turn leads to more dephosphorylation etc.
84
Q

What two features of CDK cyclin complexes/cell cycle allow the same Cdk to be used in different stages of the cell cycle

A

Different cyclins change the complex:
when cyclin binds to Cdk is actually changes the substrate specificity so that it can phosphorylate different substrates depending on which cyclins are bound to it
- It also changes substrate accessibility – The substrates available in G1/S will be different to those available in S

85
Q

What CDKs cyclin complex is G1/S

A

Cdk2 and cyclin E

86
Q

Cdk2 and cyclin E regulated which stage of the cell cycle

A

G1/S

87
Q

What CDKs cyclin complex is S

A

Cdk2 and cyclin A

88
Q

Cdk2 and cyclin A regulates which stage of the cell cycle

A

S

89
Q

What is one of the key jobs of c-Myc

A

stimulate transcription of CYCLIN D

90
Q

What does Cyclin D do

A

CYCLIN D Triggers cell cycle by ACTIVATing Cdk4 AND Cdk6

91
Q

What does cyclin D bind to

A

Cdk4 and Cdk6

92
Q

What part of the cell cycle is Rb present

A

All of it

93
Q

What does Rb have bound to it in it’s inactive state

A

transcription factors called E2F

94
Q

What does the Cdk4/Cdk6-Cyclin D complex target

A

Rb

95
Q

What causes the formation of the Cdk4/Cdk6-Cyclin D complex

A

Myc induction

96
Q

What does the Cdk4/Cdk6-Cyclin D complex do to Rb

A

starts to phosphorylate the Rb protein and as it becomes phosphorylated it loses affinity for E2F and releases E2F

97
Q

What does E2F do, what is one of its main targets

A
  • E2F transcription factors can then bind to proteins of genes in the nucleus that are involved in cell cycle progression
  • One of the E2F targets is the gene for cyclin E- the next cyclin that is required for cell cycle progression
98
Q

Rb acts as a ‘X’ in the cell cycle….

A

Brake

99
Q

Summarise the activity of Rb, starting with Myc being activated

A
  • Myc turns on cyclin D, which complexes with Cdk4/6
  • This Cdk4/6-cyclin D complex phosphorylates Rb and allows E2F to start being released into the cytoplasm and then this stimulates the production of cyclin E
  • Cyclin E forms a complex with Cdk2 which further phosphorylates Rb leading to further increase in E2F
  • This increase in E2F concentration means that it can now bind targets with lower affinity
  • This cycle continues throughout the cell cycle
100
Q

Names of the 2 CDK inhibitor families?

A
  • INK4

- CIP/KIP

101
Q

When are INK4 CDK inhibitors active

A

in G1- they inhibit Cdk4/6 by displacing cyclin D

102
Q

How do INK4 CDK inhibitors work

A

When are INK4 CDK inhibitors active

103
Q

When are CIP/KIP CDK inhibitors active

A

S Phase- they inhibit Cdk/cyclin complexes by binding to them

104
Q

How do CIP/KIP CDK inhibitors work

A

S Phase- they inhibit Cdk/cyclin complexes by binding to them

105
Q

Genes that are commonly lost in cancers are ….

A

tumour suppressor genes

106
Q

Genes that are commonly overexpressed/over-produced in cancers are ….

A

oncogenes

Cancer Y2 (15 decks)

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