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Canc > Cancer 5: signalling mechanism of growth and division > Flashcards

Cancer 5: signalling mechanism of growth and division Flashcards

1
Q

T/f most adult cells are constantly dividing

A

Most adult cells are not constantly dividing.In the absence of growth signals they go into the G0, or quiescent, phase (e.g. liver hepatocytes)

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2
Q

What is c-Myc

A

An oncogene….- transcription factor - stimulates the expression of cell cycle genes

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3
Q

When might c-Myc increase

A

In response to presence of growth factor

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4
Q

What are the key components of signalling pathways

A

Regulation of enzyme activity by protein phosphorylation (kinases)

Adapter proteins

Regulation by GTP-binding proteins

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5
Q

What is mitogenic growth factor

A

(i.e. growth signals from other cells, e.g. Hepatocyte Growth Factor released after liver damage)

Activate the kinase cascade

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6
Q

Outline the stages following growth factor binding

A

Receptor protein tyrosine kinase

Small G (GTP-binding) protein (Ras)

Kinase cascade

Immediate early genes
(c-Jun, c-Fos, c-Myc - transcription factors) – control the expression of other genes

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7
Q

What happens in response to phosphorlation of tyrosine on growth factor receptors

A

Binding of adaptor proteins

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8
Q

What can happen in HER2-positive preast cancer

A

HER2/EGFR (both ErbB receptor family, oncogenes) activated or overexpressed in breast cancers

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9
Q

What drugs can be used in HER2-positive breast cancer

A

Anti-HER2 Ab

Herceptin

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10
Q

Name an important adaptor protien

A

Grb2

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11
Q

What is a protein domain

A

functional and structural units that are copied in many proteins

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12
Q

What type of domains do adaptor proteins contain

A

domains are important in molecular recognition – have no enzymatic function of their own, simply bring other proteins together

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13
Q

What domains do Grb2 contain and which is this important

A

2 x SH3… to proline rich regions

SH2… to phosphoylated tyrosines (inducible, specific sequence context), I.E. THE PHOSPHORYLATED TYROSINES IN THE RECEPTOR

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14
Q

What is Src homology regions

A

The domains on Grb2 where first found on the src oncogenes

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15
Q

How can RAS be activated and switched off

A

Exchange factor (i.e. SOS) can cause activation of RAS by exchange of GTP for GDP

GTPase Activated Proteins will remove phosphate to switch off

NOT KINASE

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16
Q

What will happen in response to GF activation

A

Activated receptor tyrosine kinase…

binding of Grb2, Sos binds (it’s always bound Grb2 via SH3 domains)… this activates RAS by binding GTP to RAS

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17
Q

What must RAS do to be actiated

A

Ras must bind to the plasma membrane to become activated

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18
Q

Outline how RAS could be constitutively actived

A

V12RAS…. glycine 12 –> Valine
(prevents GAP binding, prevents inactivation)

L61 RAS glutamine 61–> Leucine prevents GTP hydrolysis

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19
Q

How does Ras activate protein kinase cascade

A

Specifically - Extracellular signal-regulated kinase (ERK) cascade

(Generically - Mitogen-activated protein kinase (MAPK) cascades)

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20
Q

Outline the specific ERK casade

A

(active Ras protein –>) Raf, MEK, ERK

MAPKKK, MAPKK, MAPK

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21
Q

What is B-Raf

A

B-Raf is an oncogene - mutationally activated in melanomas

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22
Q

What can happen in response to the signalling cascade

A

Changes in protein activty/changes in expression

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23
Q

What genes could ERK avticate

A

c-Myc, cell

proliferation

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24
Q

Give two examples of oncogenes fromt he ERK cascade

A

Myc and Ras are “oncogenes

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25
Q

What is cell cycle control based on

A

cyclically activated protein kinases….. called

Cyclin-dependent kinases (Cdks)

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26
Q

When are Cdks present

A

Present in proliferating cells throughout

cell cycle

27
Q

How are Cdks regulated

A

Interaction with cyclins

Phosphorylation (activating and inhibitory)

28
Q

When are cyclins present

A

Transiently expressed at specific

points in the cell cycle

29
Q

How are cyclins regulated

A

Regulated at level of expression

Synthesised, then degraded

30
Q

What do activated Cdks do

A

They phosphorylate proteins (on Serine or Threonine) to drive cell cycle progression

Serine-threonine kinases

31
Q

What does cdk1 bound with cyclin B do

A

Cyclin B is a mitotic cyclin

Nuclear lamins (causes breakdown of nuclear envelope)

32
Q

What does Cdk2 bound to cyclin E do

A

Cyclin E is a G1 cyclin, so this is causing the cell to begin

Phosphorylates retinoblastoma protein (pRb)

Tumour suppressor - inactivated in many cancers

Cyclin E/CDK2 phosphorylates retinoblastoma protein (Rb) to promote G1 progression. Hyper-phosphorylated Rb will no longer interact with E2F transcriptional factor, thus release it to promote expression of genes that drive cells to S phase through G1 phase

33
Q

T/f binding of cyclin alone will activate the cdk and why

A

F….

Requires activating phosphorylation
AND
removal of inactivating phosphorylation

34
Q

What is the 3 ways of controlling activation of cdk

A

Clycin, phsophorylation and removal of inactivating phosphorylation

35
Q

What proteins give activating phosphrylation to Cdk

A

CAK

36
Q

What proteins might give inhibitory phosphrylation to Cdk

A

Wee1

37
Q

What is the function of Cdc25 and when does it work

A

Phosphatase (this is how the Cdk1 is activated, following cyclin binding and addition of activating phosphate by CAK)

Removes the wee1 kinase (dephosphorylation activates Cdk1 at the end of interphase), so that nuclear membrane can breakdown )

38
Q

How do checkpoint signals from kinetochores influence Cdks

A

Signal from fully attached kinetochores
causes cyclin B to be degraded:

Cdk1 inactivated

key substrates dephosphorylated

mitosis progresses

39
Q

What is the function of Cdk1/cycB, when is it active

A

So when Cdk1/cycB becomes active, it moves the cell from G2 to M phase. However, whilst Cdk1/cycB is activated, the cell cannot move beyond metaphase of the M phase

It keeps mitosis ‘on hold’ until all the key substrates for metaphase have been activated

40
Q

When does Cdk1/cyclin B become inactive

A

Once all the key substrates have been phosphorylated …

41
Q

How is Cdk1/cyclin B inactivated

A

Signal from fully attached kinetochores
causes cyclin B to be degraded

SO THIS IS THE BASIS OF THE METAPHASE CHECKPOINT!

Cyclin B will not be degraded until the bubs proteins etc. have dissociated

EMAIL

42
Q

What do cyclins to do Cdk

A

Cyclins activate Cdks but also alter substrate specificity

substrate accessibility changes through cell cycle

43
Q

Outline overall how growth factor moves the cell out of G0 into G1

A

Production of ERK upregulates early gene transcrptipn factors e.g. c-Myc, c-Fos and c-Jun)

c-Myc transcription factor then stimlates transcription of other genes E.G. CYCLIN D!

44
Q

What is cyclin D1….

A

Oncogene overexpressed in 50% of breast cancers

45
Q

Which cdk must cyclin D bind to to move the cell out of G0?

A

Cdk 4/6

46
Q

Cyclin D/Cdk4/6 stimulates expression of what

A

cyclin E, to give direction and timing to the cycle (i.e. it moves it into the next stage)

47
Q

What is the effect of the regulated expression of cyclins/Cdks

A

Cdks become sequentially active and stimulate synthesis of genes required for next phase, e.g. cyclin D/Cdk4/6 stimulates expression of cyclin E – gives direction and timing to cycle

48
Q

State the cyclin/Cdk complex at each stage

A

From G0 to G1 (Cdk4/6/cycD)

From G1 to S (G1/S-Cdk transition….. Cdk2/cyclin E)

During S (S-Cdk….. Cdk2/cyclin A)

Up to metphase of mitosis (M-Cdk….. Cdk1/cycB)

DEAB (dogs eat abused bitches)

49
Q

How does cyclin D/Cdk4/6 cause cyclin E production

What is the importance of retinoblastoma protein

A

It phosphorylates retinoblastoma protein, inactivating it, allowing E2F transcription factor to transcribe cyclin E

pRb acts as a “brake” on the cell cycle in G0

Cdks phosphorylate (at multiple sites) &progressively inactivate pRb

Rb is a “tumour suppressor”

50
Q

How does cyclin4/6-cyclinD affect Rb

A

So c-Myc has been activated due to ERK, and now cyclin D has been upregulated and complexed with cyclin…..

It phosphoylates the pRb, inativating it, releasing E2F, a transcrpttion factor, which then allows gene transcription of cyclin E…. the next cyclin required for the cycle!

51
Q

Which genes are regulated by the transcprtion factor E2F

A

Protononcogenes (c-Myc, N-myc)

Cell cycle genes (retinoblastoma protein=pRb, E2F-1,2,3 cyclin A, cyclin E, CDK2, CDK4)

DNA synthesis (thymidine kinase etc.)

NOTE THAT IS IT NOT a TF to upregulate cyclin B (i.e. for the G2–>M phase… you can see on the slide that it is a transcription factor for the preceding cyclin E and A, but not B. It is also not a transcription factor for cyclin D. c-Myc, which is what binding of the mitogenic growth factor upregulated transcription of through the ERK cascade, causes upregulation of cyclin D and that’s really what sets this cycle off!

52
Q

Outline the concept of the molecular clock

A

Just look at slide 32….

basically, with the formation of each complex, pRb is phosphorylated ever more, which allows ever more E2F to be liberated and transcribe cyclins in the next stage (E then A)

Then when pRb has been phosphorylated a lot, it can activate transcription factors (not E2F, as this does not activate cyclin B, look on slide 31, cyclin B not there ) which can lead to cyclinB/cdk1 expression

53
Q

In addition to cyclins and phosphylation, how else can Cdks be regulated

A

Cdk Inhibitors (CKIs)

54
Q

Outline the two CKI families

A

INK4 family:

CIP/KIP family:
p21CIP1/WAF1
p27KIP1
p57KIP2

55
Q

What stage of the cell cycle do INK4 and CIP/KIP families of Cdk inhibitors inhibit

A

INK4- G1 phase CKIs
Inhibit Cdk4/6 by displacing cyclin D

CIP/KIP - S phase CKIs
Inhibit all Cdks by binding to the Cdk/cyclin complex

56
Q

When is there degradation of INK4

A

These are Cdk inhibitors which inhibit Cdk4/6/cyclin D and are degraded in the G1 (to stop this from being prevented)

57
Q

When is there degradation of CIP/KIP

A

These are Cdk inhibitors which inhibit all Cdks by binding to the Cdk/cyclin

And they inhibit the S phase so are degraded during S phase (Cdk2/cyclin A and Cdk2/cyclin E )

58
Q

Outline how loss of Cdk inhibitors can affect cancer

A

Loss of a certain INK4 molecule is present in up to 80% of pancreatic cancer and ALL (the p16INK4a)

59
Q

How can cyclin D be implicated in cancer

A

Overproduction of cyclin D involved in 50% of breast cancer and 90% of mantle cell lymphoma

Overproduction of Cdk4 involved in 40% of glioblastoma

60
Q

How can retinoblastoma be involved in cancer

A

LOSS of Rb involved in 80% of small cell lung cancer

61
Q

Thus, what type of genes are INK4, Cdk4, cyclin D and Rb

A

INK4, Rb tumour suppressor

Cdk4/cyclin D oncogenes

62
Q

How many members of INK4, and how many of CIP/KIP

A 
INK4= 4 members 
CIP/KIP= 3 members
63
Q

T/F Ras is a G protein

A

This is true.

It binds GTP

Canc (16 decks)

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