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Year 2 - MCD Cancer > Signalling Mechanisms > Flashcards

Signalling Mechanisms Flashcards

1
Q

Most adult cells are NOT constantly dividing - explain this, using reference to a molecule

A

In the ABSENCE of growth signals, they go into
• G0
OR
• Quiescent phase (e.g. liver hepatocytes)

c-Myc = ONCOGENE
• TF that stimulates expression of cell cycle genes
• [c-Myc] is LOW in quiescent phase
• [c-Myc] is HIGH when cell division is triggered
• OVERexpressed in many tumours

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2
Q

Key components of signalling pathways?

A
  1. Regulation of enzyme activity by protein phosphorylation (kinases)
  2. Adapter proteins
  3. Regulation by GTP-biding proteins
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3
Q

Explain how Signalling Pathways are stimulated by GFs

A
  1. Mitogenic GF (e.g. hepatocyte GF) binds to receptor
    • receptor protein is tyrosine kinase
  2. GF acts via. a small GTP-biding protein (Ras)
    • triggers the kinase cascade
  3. This triggers the activation of immediate, early genes required for progression of cells through the cell cycle
    • c-Jun, c-Fos, c-Myc are the TFs
    • this process is SLOWER as it requires transcription/translation
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4
Q

Explain how the Signalling Pathways are stimulated by Peptide GFs

A
  1. The phosphorylated RPTK recruits adaptor & signalling proteins (e.g. Grb2)
    • RPTK = Receptor Protein Tyrosine Kinase
  2. Dimeric GF binds to & draws together the RPTK
    • cross-phosphorylation occurs using ATP
  3. The phosphorylated domains acts as docking sites for adaptor proteins
    • these proteins contribute to signalling downstream
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5
Q

What is an important adaptor protein used in signalling pathways?

A

Grb2

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6
Q

Explain what Herceptin is?

A

Anti-Her2 antibody

Blocks early growth

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7
Q

What are adaptor proteins?

A

APs are often modular
• different domains are mixed & matched to give the protein different properties

This property is important in molecular recognition
AND
Adaptor molecules have NO enzymatic function
• simply bring other proteins together

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8
Q

Explain the interactions that Grb2 has

A

Has ONLY 2 types of protein-protein interaction

  • SH2 - binds to phosphorylated tyrosine of receptor (inducible)
  • SH3 - bind to proline rich regions of other proteins (constitutive)
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9
Q

Explain how GTP-binding proteins are seen as molecular switches

A

Ras!
• Grb2 brings Ras onto the RTK
• It is a GTP-binding protein (powerful molecular switch)
• It is either ON (GTP-bound) OR OFF

Exchange factors = ON
GTPase activating proteins = OFF

Most Ras in a cell is OFF
• in cancer, the Ras protein may be mutated and constantly in the GTP-bound state –> signals

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10
Q

What type of proteins are GTP-binding proteins not?

A

They are NOT kinases!

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11
Q

Explain another way Ras can be activated using Adaptor Proteins

A

RPTKs signal to Ras

Grb2 is bound to RTPK via. SH2 domain
• Ras is ALWAYS bound to Grb2
AND
SH3 region is bound to Sos
• Sos allows exchange of GDP –> GTP (turns Ras ON)
• This changes conformation of Ras & activations of signals from Ras

Ras sits in the membrane of the cell - must bind to the plasma membrane to become activated

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12
Q

Ras can suffer from mutations - explain this, giving the 2 ways it can occur

A

Ras can be oncogenically activated by mutations that INCREASE the amount of active GTP-loaded Ras

2 ways this can happen
• V12Ras - glycine in position 12 –> valine
- PREVENTS GAP binding so prevents inactivation

• L61Ras - glutamine is position 61 –> leucine
- PREVENTS GTP hydrolysis

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13
Q

Once Ras has been switched on via. either of the 2 mechanisms, what then occurs?

A

Ras ACTIVATES ERK cascade (a form of a MAPK cascade)
• ERK = EC Signal-Regulated Kinase
• MAPK = Mitogen-Activated Protein Kinase

The Ras then DIRECTLY initiates the kinase cascade where EACH kinase activated ANOTHER kinase

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14
Q

What is specifically involved in the ERK cascade?

A

3 kinases are specific to the ERK cascade
• Raf (MAPKKK)
• MEK (MAPKKK)
• ERK (MAPK)

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15
Q

In general, what do PKs do?

A

STIMULATE
• changes in cell proteins
&
• gene expression

TO PROMOTE DIVISION

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16
Q

When the last kinase is phosphorylated, what occurs?

A

Several proteins change their activity
• e.g. TFs
which then regulate gene expression

E.g. of a gene that is stimulated is the c-Myc gene

Myc & Ras are KEY ONCOGENES that may be mutated in human tumours

17
Q

What is Cell Cycle control based on?

A

Cdks

cyclin-dependent kinase

18
Q

Describe Cdks

A

Cyclin-dependent kinase
• Present in proliferating cells throughout the cell cycle

Activity is regulated by i
• interaction with cyclins
&
• phosphorylation

19
Q

What are Cdks not?

A

These are NOT TKs (these are serine-theronine kinase)

20
Q

Describe Cyclins

A

Transiently expressed
• only expressed at specific points in the cell cycke

Regulated at level of expression

Once they are synthesised (i.e. activate a Cdks), they degrade

21
Q

Explain the relationship between Cdks & cycline

A

Cyclin(s) bind to & activare Cdk(s), triggering different events in the cell cycle

• e.g. M-phase-promoting factor initiates mitosis
- Mitosis Promoting Factor = Cdk1 + Mitotic cyclin B

22
Q

What do activated Cdks go on to do then?

A

They phosphorylate proteins (on Serine OR Theronine) to drive cell cycle progression

e. g. Nuclear lamins - causes NE breakdown
- Cdk1 + Cyclin B (mitotic cyclin)

e. g. Retinoblastoma protein - tumour supressor (inactivated in many cancers)
- Cdk2 + Cyclin E (G1 cyclin)

23
Q

What regulates Cdks?

A

Although cyclin show a cyclical nature of expression, so can track synthesis & degradation in a predictable way:

PHOSPHORYLATION regulates Cdks

24
Q

How are Cdks regulated?

A

PHOSPHORYLATION regulates Cdks

e.g. Cdk1 binds to Cyclin B which is INACTIVE until phosphorylated by 2 reactions:

• Cdk Activating Kinase (CAK)
= activating
&
• Wee1 = a Balancing Inhibitor (add phosphates)
= inhibitor
= Cdc25 then REMOVES the Wee1 inhibitory phosphate (to allow activation)

25
Q

How is Wee1 then handled to allow for activation of Cdks?

A

Dephosphorylation of the inhibitor Wee1 phosphate
• activates Cdk1 at the end of interphase

Active MPF then phosphorylates Cdc25 to increase its activity
• drives a +VE feedback
• this helps drive mitosis as dephosphorylates Wee1

MPF = Mitosis Promoting Factor

26
Q

General overview of Mitosis in terms of the signalling pathways?

A

MPF at the END of metaphase
• phosphorylates key substrates in the mitotic process
• puts mitosis on HOLD whilst substrates are phosphorylated

One the kinetochores are attached, a signal is released
• causes cyclin B to be degraded
• this causes Cdk1 to become inactive
• means the substrates are dephosphorylated
• mitosis can now PROCEED

27
Q

Cyclins and Cdks at different stages of the cell cycle?

A

DIFFERENT cyclins & Cdks required at different stages of the cell cycle
• e.g. G1/S = Cdk2, Cyclin E
• e.g. S = Cdk2, Cyclin A

Note how the same Cdk is bound BUT with a diff. cyclin
• cyclin therefore changes the substrate specificity (to phosphorylate different substrates)

28
Q

Using Cdks, how is the cell cycle triggered

A

Growth factor stimulation of signalling pathways promotes G0 to G1 transition:
• GF binds to the RPTK –> cascades via Ras
• transcription factor phosphorylation –> expression of c-Myc
• stimulate transcription of cyclin D

Cyclin D activates Cdk4 and Cdk6
• goes on to synthesis of Cyclin E
• this triggers the cell cycle

29
Q

How is there regulated expression of cyclins/Cdks?

A

Each Cdk produced is involved in stimulating synthesis of the next Cdk by stimulating synthesis of genes required
• e.g. Cyclin D/Cdk4/6 –> Cyclin E
• gives direction and timing to cycle

Cyclins are susceptible to degradation, hence cyclical activation

30
Q

Gene expression can also be regulated by Rb, explain how

A

pRb - protein retinoblastoma

pRb acts as a “brake” on the cell cycle.
• Cdks phosphorylate & progressively inactivate pRb
• Rb is a “tumour suppressor”.

MoA:
• In G0, Rb protein is resting with E2F transcription factors in the cell cytoplasm
• Cdk4/6-cyclin D kinase phosphorylates Rb and E2F is released and binds to gene promoters to drive transcription

31
Q

Explain the relationship between Rb, E2F and cyclin E

A

One target of E2F is the cyclin E, the cyclin required to continue cell cycle progression
• Rb acts as a brake in the cell cycle by holding onto the E2F – this makes it a TUMOUR SUPRESSOR GENE.

Many tumours have reduced levels of Rb protein so can’t regulate E2F

32
Q

Describe and explain the E2F TFs

A

E2F regulate proto-oncogenes
• includes Myc proteins

Cyclin E is one of the FIRST targets of E2F –> pushes the cell cycle forward
• Cyclin E –> binds to Cdk2
• “CyclinE-Cdk2 complex” phosphorylates Rb protein so another +ve feedback is initiated so more E2F is released by Rb

33
Q

Explain the order that the cyclins and Cdks are switched on

A

Myc turns on cyclin D which complexes with Cdk4/6…
• Cyclins – D –> E –> A –> B.
• Cdks – 4/6 –> 2 –> 2 –> 1.

Ultimately leads to mitosis.
• more and more pRb is phosphorylated to release more E2F (which is what initially creates cyclin E).
• Cyclin A gene promoter is not activated until there is a HIGH concentration of E2F

34
Q

Cdks are also regulated by something else - explain what it is and the two families

A

Cdk Inhibitors

Two families of Cdk-Is exist:
• INK4 family - e.g. p15(INK4b)
- G1-phase Cdk-I
- Inhibits Cdk4/6 by displacing Cyclin D

• CIP/KIP family - e.g. p21(C1P1)

  • S-phase Cdk-I
  • Inhibits all Cdks by binding to the Cdk/Cyc complex

For the cell cycle to progress, these inhibitors need to be DEGRADED

35
Q

What type of genes are commonly LOST in cancers?

A

TUMOUR SUPRESSOR GENES

  • Rb – inactivated in many cancers.
  • P27KIP1 – under expression correlates with poor prognosis
36
Q

What types of genes are commonly OVER-EXPRESSED in cancers?

A

ONCOGENES

  • EGFR/HER2 – mutation activated in breast cancer – treated with Herceptin antibody (in HER2+ cancer)
  • Ras – mutation activated – treated with membrane attachment inhibitors
  • Cyclin D1 – overexpressed in 50% of breast cancer
  • B-Raf – mutation activated in melanomas – treat with kinase inhibitors
  • cMyc – overexpressed in many tumours

Year 2 - MCD Cancer (14 decks)

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