Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Cancer > 5. Signalling mechanisms in growth and division > Flashcards

5. Signalling mechanisms in growth and division Flashcards

1
Q

What is c-Myc?

A

• (Proto-)oncogene + transcription factor
• As soon as growth factor binds to cells, c-Myc is expressed
• Over-expressed in many tumours
- stimulation to express cell cycle genes

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

Outline the expression of c-Myc throughout the cell cycle

A
  • Low conc. in G0
  • If you trigger cell division, rapid and dramatic rise in Myc
  • Peaks then goes down going into the S phase
  • Plateaus at intermediate level in the S phase
  • Stays at that level into G1
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What binding protein does a growth factor act via when it binds to a (tyrosine kinase type) receptor and what does this trigger?

A
  • GTP-binding protein (Ras)
  • This triggers a kinase cascade (fast)
  • Activation of genes required for the progression through the cell cycle (slow - requires transcription + translation)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

At what point of the signalling pathway is c-Myc triggered?

A

Early in the kinase cascade

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

What are mitogenic growth factors?

A

Growth factors that induce mitosis in cells

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

What is herceptin, what does it do and why is it important in tumours?

A
  • Anti-HER2 antibody
  • Blocks the early stage of growth stimulation
  • Important as HER2 can be over-expressed in a number of tumours e.g. breast cancer
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What are one of the important adaptor molecules that are recruited to activated tyrosine kinase receptors?

A

Grb2 - important for bringing Ras onto the signalling unit

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

Which part of ATP do tyrosine kinases use to phosphorylate tyrosine residues in proteins?

A

Gamma phosphate of ATP

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

What do the phosphorylated domains on the tyrosine kinase receptors act as?

A

Docking sites for adaptor proteins

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

Describe function of the domains of adapter proteins

A
  • Functional/structural units that are copied in many proteins
  • Mixed and matched to give the protein different properties
  • Important in molecular recognition
  • No enzymatic function - only bring proteins together so enzymes and substrates meet
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

How many domains does Grb2 have and what are they?

A
  • 3 domains
  • SH2 - binds to the phosphorylated tyrosines of the receptor
  • (2x) SH3 - binds to the proline-rich regions of other protiens
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is Ras?

A
  • GTP-binding protein (+ pro-oncogene)

* Can either be on (GTP-bound) or off (GDP-bound)

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

Is the switching on of Ras phosphorylation?

A
  • No

* Merely the exchange of GDP for GTP (catalysed by Sos)

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

How can Ras turn itself off?

A

Can hydrolyse GTP do GDP itself (intrinsic GTP hydrolysis capability)

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

How can Ras be turned on and off externally?

A
  • On - Exchange factors e.g. Sos
  • Off - GTPase activating proteins (GAPs)

Almost always control the cycle

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

Are the GTP binding proteins kinases?

A

No

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

What happens to Ras in cancer?

A
  • Mutated to always be in the GTP bound form

* Leads to uncontrolled division

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

Which domain is Grb2 bound to the RPTK via?

A

SH2 domain

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

Which domain is Grb2 bound to Sos via?

A

SH3 domains

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

Outline how the activation of RPTK leads to the activation of Ras?

A
  • RPTK activated - phosphorylated
  • Grb2, with Sos attached, binds to the phosphorylated tyrosine domains
  • Sos is then close enough to the membrane to activate Ras (GDP => GTP)
  • Activated Ras can signal downstream
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Where does the Ras protein need to be bound to work?

A

Plasma membrane (interference with this can make a good anti-cancer therapy)

22
Q

What does V12Ras describe, with reference to mutations?

A
  • Glycine => valine (position 12 of Ras)
  • Simple hydrogen => hydrophobic side chain
  • Prevents GAPs from binding to Ras
  • Ras can’t be turned off easily and constantly gives growth stimulatory signals
23
Q

What does L61Ras describe, with reference to mutations?

A
  • Glutamine => leucine (position 61 of Ras)
  • Single base change
  • Amide => hydrophobic side chain
  • Prevents intrinsic GTPase hydrolysis
  • Ras is constantly turned on and giving growth stimulatory signals
24
Q

What is the specific kinase cascade for growth stimulatory signalling and the generic name for the cascades?

A
  • Growth stimulatory signalling: extracellular-signal-regulated kinase (ERK) cascade
  • Generic: mitogen-activated protein kinase (MAPK) cascade
25
Q

Which oncogene can be blocked to temporarily prevent melanomas from growing?

A

B-Raf

26
Q

What are cyclin-dependent kinases?

A
  • Family of kinases
  • Serine-threonine kinases (not tyrosine kinases)
  • In the cell throughout the cell cycle
  • Not active until they bind to cyclin
  • Also controlled by phosphorylation (extra level of control)
27
Q

Describe how cyclins work

A

• Transiently expressed during the cell cycle (specific points of the cell cycle)
• Expressed during mitosis
• Cyclins dock onto the cyclin-dependent kinases => activate them
• Activated CDKs phosphorylate proteins
• Degrade once they activate the CDKs and it has fulfilled its role
- low during interphase, then rise again into mitosis

28
Q

What is the M-phase promoting factor?

A
  • A type of cyclin-CDK complex (cyclin B/mitotic cyclin + CDK1)
  • Triggers the mitotic machinery
29
Q

What happens when S-cyclin binds to CDK?

A
  • Induces protein synthesis

* Triggers DNA replication machinery

30
Q

Give an example of the substrates that M-phase promoting factor phosphorylates and the effect this has

A

Nuclear lamins (proteins that form the nuclear membrane) => this breaks down the nuclear envelope

31
Q

Describe how the cyclin-CDK complex is further activated in MPF?

A
  • CDK activating kinase (CAK) => activating phosphorylation of CDK1
  • Wee1 => inhibitory phosphorylation of CDK1 to balance this
  • Cdc25 (phosphatase) then takes off the inhibitory phosphate put on by Wee1
  • MPF is activated
  • Active MPF can phosphorylate Cdc25 to increase its activity (positive feedback) => pushes cell through mitosis to metaphase
  • Mitosis is then put on hold
32
Q

When is a signal released to cause cyclin B to be degraded?

A
  • When kinetochores are correctly attached to the microtubule spindles => CDK1 becomes inactive
  • Mitosis can then progress from metaphase
33
Q

Which cyclins and CDKs control G1/S and S?

A
  • G1/S - cyclin E + CDK2

* S - cyclin A + CDK2

34
Q

What does cyclin do to CDK to activate it?

A

Changes its substrate specificity and accessibility - so it phosphorylates different substrates depending on which cyclins are bound

35
Q

Which cyclin does c-Myc stimulate the transcription of?

A

cyclin D

36
Q

What does cyclin D do?

A
  • Binds to CDK4 and CDK6
  • Controls the entrance to the cell cycle
  • Therefore (c-Myc and) cyclin D regulates the G0 => G1 transition
37
Q

What does cyclin D/CDK4/CDK6 stimulate the expression of and what does this do?

A
  • cyclin E
  • Gives direction and timing to the cycle
  • Gives timing as it takes time for the conc. of the cyclin to build up
38
Q

What is the retinoblastoma protein and describe how it works?

A
  • Tumour suppressor protein (acts as a brake in the cell cycle)
  • Present throughout the cell cycle
  • Unphosphorylated (active) in G0
  • Binds to and sequesters (hides) E2F (transcription factor)
  • E2F is held in the cytoplasm and everything is turned off
  • CDK4/6-cyclin D kinase becomes active following c-Myc induction
  • It phosphorylates the retinoblastoma protein (inactivation)
  • RB loses affinity for E2F and releases it
  • E2F can bind to promoter of genes involved in cell cycle progression (in nucleus) e.g. gene for cyclin E
39
Q

What happens to the levels of retinoblastoma protein in tumours?

A

Reduced levels => E2F activity unregulated => cell cycle progression uncontrolled

40
Q

What genes does E2F transcription factor control?

A
  • Proto-oncogenese e.g. Myc proteins
  • Genes involved in the S phase e.g. thymidine kinase
  • cyclin E
41
Q

Summarise the progression from c-Myc to cyclin E

A
  • c-Myc turns on cyclin D
  • cyclin D complexes with CDK4/6
  • The complex phosphorylates retinoblastoma, deactivating it
  • Inactive RB releases E2F
  • E2F stimulates the production of cyclin E
42
Q

What does cyclin E do?

A
  • Forms complex with CDK2
  • Complex further phosphorylates retinoblastoma protein
  • Further increase in E2F - to the point it now binds to targets with lower affinity
  • cyclin A starts to be transcribed instead
  • cyclin A leads to the production of a transcription factor that causes cyclin B-CDK1 complex to be formed
  • Mitosis induced
43
Q

What are the 2 families of CDK kinase inhibitors (CKIs)?

A
  • INK4

* CIP/KIP

44
Q

What do CDK kinase inhibitors (CKIs) do?

A
  • Proteins that dock onto the cyclin-CDK complex

* Render it inactive

45
Q

When are INK4 inhibitors active and what do they do?

A
  • Active in G1

* Inhibit CDK4/6 by displacing cyclin D

46
Q

When are CIP/KIP inhibitors active and what do they do?

A
  • Active in S phase

* Inhibit all the cyclin-CDK complexes by binding to them

47
Q

What is p27KIP1 and what does reduced expression correlate with?

A
  • Tumour suppressor in the CIP/KIP family of CKIs

* Reduced expression correlates with poor prognosis in many malignancies

48
Q

Are CDK kinase inhibitors (CKIs) degraded?

A

Yes, they have to in order for the cell cycle to progress

49
Q

Are cell surface tyrosine receptors oncogenes or lost tumour suppressor genes in cancer?

A

Oncogenes e.g. mutationally activated or over-expressed HER2

50
Q

Is Ras mutationally activated or over-expressed in cancers?

A

Mutationally activated

Cancer (15 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions