Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

MCD Cancer > Signalling Mechanisms of Growth and Division > Flashcards

Signalling Mechanisms of Growth and Division Flashcards

1
Q

what is c-Myc and what does it do?

A

a transcription factor that stimulates expression of cell cycle genes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what are c-Myc levels in the quiescent phase and cell division phase?

A

Concentration of Myc is low in the quiescent phase and then in triggered cell division, Myc rapidly rises

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what are the 3 components of the signalling pathway?

A
  1. Regulation of enzyme activity by protein phosphorylation – kinases.
  2. Adapter proteins.
  3. Regulation of GTP-binding proteins.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

how is the signalling pathway stimulated at first?

A

by growth factor which triggers a kinase cascade

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what is the main effect of the kinase cascade?

A

the activation of immediate early genes (which c-Myc affects) required for the progression the cell cycle (transcription and translation)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what does the phosphorylated receptor protein tyrosine kinase (RPTK) recruit?

A

the adaptor molecule
e.g. Grb2
and signalling proteins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what is the action of the dimeric Growth Factor (GF)?

A

draws together two tyrosine kinase receptors which then cross-phosphorylate using ATP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

where do adaptor proteins bind?

A

to the phosphorylated domains which act as docking sites

e.g Grb2

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

example of substance that can block the binding of the dimeric growth factor?

A

Herceptin (anti-Her2 antibody) blocks growth early

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what gives adaptor proteins different properties?

A

Different domains are mixed and matched to give the protein different properties. Important in molecular recognition

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

do adaptor proteins have enzymatic functions?

A

molecules have no enzymatic function; they simply bring other proteins together.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what are type of interactions that Grb2 make?

A

o SH2 – binds to phosphorylated tyrosine of receptor.
o SH3 – bind to proline rich regions of other proteins.

SH2 is important here

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what is the role of adaptor protein in relation to the RTK?

A

brings in the Ras (a GTP binding protein)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What sort of molecule is Ras?

A

a GTP binding protein which is switched on when attached to GTP and switched off when there is no GTP (GDP instead)

it is not a kinase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

in what conditions is Ras active?

A

has to be bound to the plasma membrane

then must have a GTP bound

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what enables GTP to bind to Ras?

A

exchange factors e.g. Sos

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what switches off Ras?

A

GTPase Activating Proteins (GAPs) that hydrolyse the GTP to GDP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

what role does Ras play in cancer?

A

Ras is usually in the switched off position

but mutations mean it could have GTP bound all the time leading to constant cell cycle signals being made

act as oncogene

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

where does the Ras-activating protein e.g Sos bind?

A

to the adaptor protein at SH3, at all times

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what binds to SH2 and SH3?

A

adaptor protein is bound to the RTK via SH2

the Ras-activating protein (exchange factors like Sos) is ALWAYS bound to Grb2 via SH3

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

what is the effect of a Ras mutation?

A

 Ras can be oncogenically activated by mutations that increase amount of active GTP-loaded Ras.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

examples of Ras mutations

A

V12Ras – glycine in position 12 –> valine
o Prevents GAP binding so prevents inactivation. (GAP ensure GTP to GDP on Ras)

L61Ras – glutamine in position 61 –> leucine.
o Prevents GTP hydrolysis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

what is the role of activated (GTP-bound) Ras?

A

initiate the ERK (a MAPK cascade form) cascade so the kinases can activate another

phosphorylate Raf

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

what is the kinase cascade called

A

Extracellular Signal-Regulated Kinase (ERK) cascade.

same as Mitogen-Activated Protein Kinase (MAPK) cascade

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
what are the 3 kinases specific to ERK cascade?
o Raf – MAPKKK. o MEK – MAPKK. o ERK – MAPK.
26
what is the role of protein kinases?
changes in cell proteins (activity) and gene expression to promote division via phosphorylation
27
what does the ERK kinase in the ERK cascade do?
this is the last kinase in the cascade which phosphorylates proteins to change their activity e.g the transcription factors so they can regulate gene expression an example of a gene that will be expressed is c-Myc as a result of the cascade
28
what are key oncogenes that can be mutated in human cancers/tumours?
Myc and Ras
29
what proteins regulate the cell cycle (CC) ?
cyclin-dependent kinases (Cdks) these are not tyrosine kinases
30
when are Cdks present?
Present in proliferating cells throughout the cell cycle.
31
how do Cdks regulate the CC?
interaction with cyclins & phosphorylation
32
when and how are Cdks activated? how does deactivation occur?
activation by phosphorylation when bound to cyclin by: Cdk activating kinase (CAK) activation by removal of deactivating phosphorylation: - the deactivating phosphorylation = Wee1 phosphate - remover of this =Cdc25, a phosphatase after Cdk has been activated, the cyclin detaches and it degraded at the end of interphase (ready to enter mitosis)
33
when are cyclins expressed?
at specific points of the CC, regulated at the level of expression Cdks don't really change
34
how do Cdk-cyclin carry out their overall function in the CC?
there are multiple Cdk-cyclin complexes (all different) that trigger the different events of the CC
35
Cdk-cyclin complex that induced mitosis
Mitosis promoting factor (namely Cdk-1 +cyclin B) induces mitosis cyclin B is "mitotic cyclin B"
36
what is the key process that regulates Cdk?
phosphorylation and dephosphorylation | by Cdk activating kinase (CAK)
37
what causes the final activation step of Cdk1-cyclin B complex?
in mitosis: phosphatase Cdc-25 removes the inhibitor that prevents the activation of the complex despite being bound together allows progression from interphase to mitoses
38
at what stage does Cdc25 (a phosphatase) remove the Wee1 phosphate?
end of interphase when Cdk1 should be activated to go into mitosis
39
what effect does the activated Cdk1-CycB complex (aka Mitosis Promoting Factor) have on the Wee1-removing Cdc25?
phosphorylates Cdc25 to increase activity and drives a +ve feedback. it can now remove the inhibitory phosphate
40
what is the mitotic promoting factor doing at end of metaphase?
puts mitosis on hold while key substrates for the mitotic process are phosphorylated
41
what does MPF do once kinetochores have attached to the sister chromatids?
releases a signal to degrade its cyclin B
42
what happens when cyclin B is degraded?
MPF degraded Cdk1 becomes deactivated substrates are dephosphorylated so mitosis can proceed
43
what is the Cdk-cyclin complex allowing G1 to S?
Cdk2+ cyclin E
44
what is the Cdk-cyclin complex in S?
Cdk2+ cyclin E | Cdk2+ cyclin A
45
what phase is Cdk2-CycE involved in?
G1 into S
46
what phase is Cdk2- CycA involved in?
S
47
why is the cyclin different but the Cdk is the same when the CC goes from G1 to S?
same Cdk is bound but with a different cyclin so the cyclin changes the substrate specificity (to phosphorylate different substrates).
48
what does Growth Factor stimulation of the signally pathways promote?
the transition from G0 to G1
49
what is the pathway of GF to the formation of CC relating Cdk-cyc complexes?
GF binds to the RPTK --> cascades via Ras --> transcription factor phosphorylation--> expression of c-Myc--> stimulate transcription of cyclin D.
50
what Cdk does cyclin D bind to?
Cdk4 and Cdk6
51
what is the effect of cyclin D activating Cdk4/6?
the synthesis of Cyclin E (used in G1) therefore the activation of Cdk4/6 starts off the CC
52
what is the order of Cdk-Cyc complexes created starting from the effects of c-Myc?
GF--> c-Myc expression 1) Cdk4/6+CycD (G1 to S) 2) Cdk2+CycE (G1 to S where is falls) 3) Cdk2+CycA (G1 to S, falls at mitosis) 4) Cdk1+CycB (MPF, peaks at mitosis) DEAB cyclins 46221 Cdks
53
how is Cdk-cyc expression a regulated process?
Different cyclins and different Cdks are required at different stages of the cell cycle. Each Cdk produced is involved in stimulating synthesis of the next Cdk by stimulating synthesis of genes required. Gives direction and timing to cycle
54
which amino acids do Cdks target when they phosphorylate? | example of protein that is phosphorylated?
Serine or Threonine the phosphorylation of proteins drives the CC phosphorylated retinoblastoma protein (pRb) has been phosphorylated by Cdk2-CycE at these positions
55
what type of protein is the retinoblastoma protein?
Rb protein (acts as a “brake” on the cell cycle)
56
what effect does phosphorylation of a Rb protein like retinoblastoma protein (pRb) have on it?
phosphorylation of the Rb protein inactivates it
57
why do Rb proteins like pRb need to be phosphorylated to allow cell cycle progression?
Rb is a “tumour suppressor”. Phosphorylation deactivates it and therefore allows the progression of the CC
58
How does the Rb (like pRb) carry out its tumour suppressor function?
in a G0 cell, the Rb protein is in the dephosphorylated state (i.e activated Rb) in this state, the Rb inactivates the E2F transcription factors (which enables the expression of Cyclin E for the CC to progress) by binding to it NB phosphorylation of Rb does NOT allow it to do its function
59
How does the Cdk prevent the Rb carrying out its tumour suppressor function? Why must this happen?
Cdk phosphorylates the Rb protein and therefore deactivates it. This means is lets go of its E2F transcription factors that it had previously kept deactivated. The E2F TF is now active and can allow the expression of Cyclin E and therefore CC progression
60
which Cdk-Cyc complex actually phosphorylates the Rb protein to allow the expression of Cyclin E by E2F TF?
Cdk4/6-CycD
61
what gene does EF2 TF allow to be expressed?
cyclin E for the progession of the CC
62
what TF do Rb proteins hold onto?
E2F
63
what type of gene expresses Rb proteins?
tumour suppressor gene therefore reduced Rb --> tumour
64
name targets of EF2 TF?
myc proteins | cyclin E
65
Now that EF2 can allow Cyclin E expression, what effect does this have on Rb proteins downstream?
positive feedback for greater Rb deactivation: Cyclin E can form Cdk2-CycE which phosphorylates further Rb proteins and causes the release of more E2F in a +ve feedback
66
what is the concentration of E2F by the time Cyclin A can be expressed?
high
67
what are the inhibitors that regulate Cdks?
Cdk-Is in 2 families: o INK4 family – e.g. p15INK4b o CIP/KIP family – e.g. p21CIP1/WAF1.
68
what phase does the INK family of Cdk-I affect and therefore what does it do?
G1 | inhibits Cdk4/6-CycD by displacing cyclin D
69
what phase does the CIP/KIP family of Cdk-I affect and what does it do?
S | inhibits all Cdk-Cyc complexes by binding to them
70
what needs to be done to the Cdk-Is in order for the CC to progress?
they need to be degraded
71
what are the genes that are typically lost in cancers?
tumour suppressor genes: o Rb – inactivated in many cancers. o P27KIP1 – under expression correlates with poor prognosis. however p53 being a TSG is often over expressed because a mutated p53 has a poor protein turnover
72
which genes are commonly over-expressed in cancers?
oncogenes: o EGFR/HER2 – mutation activated in breast cancer o Ras – mutation activated o Cyclin D1 – overexpressed in 50% of breast cancer. o B-Raf – mutation activated in melanomas o cMyc – overexpressed in many tumours.
73
how is EGFR/Her2 over-expression treated?
– treated with Herceptin antibody (in HER2+ cancer). Stop proliferative signalling
74
how is Ras over-expression treated?
treated with membrane attachment inhibitors | needs attachment to the membrane for activation
75
how is B-Raf over-expression treated?
treat with kinase inhibitors. | one of the kinases in the ERK cascade
76
what is the purpose of the ERK cascade?
stimulate changes in cell proteins and gene expression to promote division.
77
how does p27KIP actually inhibit the Cdks?
p27KIP complexes with the Cdk4-cyclinD | - but does not inhibit its action until the complex is phosphorylated by GSK3b
78
what is GSK3b? | what is it inhibited by?
phosphorylates the p27KIP-Cdk complex to inactive the Cdk inhibited by Akt/PKB so cell cycle progression can occur
79
what is the function of SOS?
exchange factor swapping GDP on the GDP-loaded Ras for GTP to activate Ras

MCD Cancer (17 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions