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Cell signalling and proliferation > Cell proliferation > Flashcards

Cell proliferation Flashcards

1
Q

What controls the cell cycle?

A

Cyclic dependent kinases

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2
Q

What is the activity of CDKs in the cycle like?

A

Rise and fall as the cell cycle progresses

Leading to phosphorylation/ no phosphorylation of intracellular proteins that initiate events in cell cycle

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3
Q

What would an increase in CDK at G2/M checkpoint mean?

A

Increase in phosphorylation of proteins that control chromosome condensation, nuclear envelope breakdown, spindle assembly etc

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4
Q

What regulates CDKs?

A

Cyclins

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5
Q

What happens when cyclin binds to CDK?

A

Protein kinase of CDK is activated to trigger specific cell cycle events

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6
Q

Concentration of cyclins throughout cell cycle

A

Rise and fall but concentration of CDKs remain the same

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7
Q

What are the 4 types of cyclins?

A
  1. G1-S cyclins
  2. S cyclins
  3. M cyclins
  4. G1 cyclins
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8
Q

G1-S cyclins

A

Bind to CDK in late G1
Activate start phase of cell cycle
Levels fall in S phase

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9
Q

S cyclins

A

Bind to CDK in S phase
triggers chromosome duplication
Levels remain high until mitosis

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10
Q

M cyclin

A

Bind to CDK
Activates cell entry into mitosis at G2/M checkpoint
Levels fall at mid mitosis

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11
Q

G1 cyclins

A

Control activity of G1/S cyclins

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12
Q

How is CDK-cyclin complex activated?

A

When cyclin isn’t bound to CDK= active site on CDK is blocked by a slab of protein
When cyclin binds= slab of protein is removed away from active site
This partially activates CDK enzyme
Fully activated= CAK phosphorylates an a.a in CDK active site
Causes conformational change= tighter binding of cyclin and CDK
target proteins are phosphorylated

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13
Q

Which type of cyclins are found in early G1?

A

D cyclins-D1,D2,D3

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14
Q

What type of cyclins are found in late G1 (after R line)

A

E cyclins- E1,E2

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15
Q

What type of cyclins are found in S phase?

A

A cyclins- A1,A2

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16
Q

What type of cyclins are found in M phase?

A

B cyclins- B1,2

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17
Q

What do D cyclins bind to in G1?

A

CDK4/CDK6

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18
Q

What do E cyclins bind to in late G1?

A

CDK2

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19
Q

What do A cyclins bind to in S phase?

A

CDK2/CDC2

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20
Q

What do B cyclins bind to in M phase?

A

CDC2

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21
Q

What strongly influences levels of D type cyclins?

A

Extracellular signals e.g growth factors

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22
Q

How do CDK inhibitors block action of CDK?

A

CDK inhibitor binds to CDK
Stimulates large rearrangement in structure of CDK active site
Meaning it can’t bind to cyclin

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23
Q

Name of 2 CDK inhibitor proteins

A

INK4 proteins- p16INK4a, p15INK4b, p18INK4Cc, p19INK4d

CIP/KIP proteins- p21Cip1, p27Kip1, p57Kip2

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24
Q

What do INK4 CDK inhibitors do?

A

Inhibit cyclin D-CDK4/6 forming in early and mid G1

This halts cell cycle

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25
Q

What do INK4 CDK inhibitors code for?

A

Tumour suppressor genes
INK4a (CDKN2A)- codes for p16
INK4b (CDKN2B)- codes for p15
p14ARF- codes for p53

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26
Q

What is transforming growth factor- Beta? (TGF-B)

A

Proteins that regulate cell proliferation and differentiation
Have dimer proteins- type I and type II join (homodimerize)
They can inhibit cell proliferation

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27
Q

How does TGF-Beta inhibit cell proliferation?

A

They increase expression of CDK inhibitors- esepcially p15INK4b and weaky p21Cip1

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28
Q

TGF-Beta pathway

A
  1. TGF-Beta receptor binds to ligand (TGFB cytokines) TGFB receptor homodimerizes
  2. Type II receptor phosphorylates type I receptor
  3. Phosphorylated type 1 receptor recruits and phosphorylated SMAD2/3
  4. Phosphorylated SMAD2/3 dissociated from receptor and binds with SMAD4= heterotrimeric complex
  5. Complex translocates to nucleus and promotes gene expression and transcription of CDK inhibitor- p15INK4b- inhibits cyclinD-CDK4 complexes
    SMAD3 can also form complexes with other proteins to reduce MYC expression.
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29
Q

What happens when TGF-Beta receptor/SMAD is mutated?

A

No CDK inhibitors made= increase cell proliferation, tumour cells= metastasis

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30
Q

What is retinoblastoma protein?

A

Tumour suppressor protein
Encoded by Rb gene
Universal regulator of cell cycle
acts as BRAKES of the cell cycle

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31
Q

What is retinoblastoma cancer?

A

Tumour in precursor cells in the retina

Deletion/mutation in Rb

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32
Q

What happens when Rb is mutated/loses function?

A

Cell enters cell cycle inappropriately

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33
Q

What is done to Rb protein in controlling cell cycle

A

Phosphorylated

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34
Q

When is Rb NOT phosphorylated in the cell cycle?

A

M phase to G1 phase

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35
Q

When does Rb become slightly phosphorylated in the cell cycle? (hypophosphorylated)

A

R point of late G1 phase

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36
Q

When does Rb become phosphorylated? (hyperphosphorylated)

A

Once cell passes R point in G1 phase
Done by cyclin E-CDK2
Remains hyperphosphorylated till M phase

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37
Q

What does it mean if Rb is not phosphorylated?

A

Binds to transcriptional factors (E2Fs)
Prevents E2Fs from promoting genes needed to make proteins needed for DNA synthesis e.g DNA polymerase
So no DNA synthesis from M to late G1

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38
Q

How does unphosphorylated Rb prevent DNA synthesis from M to late G1 phase?

A

Rb binds to transcriptional factors
Attracts histone deacetylase
Increases affinity between DNA and histones
so transcription factors cant access DNA= no DNA synthesis

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39
Q

How does phosphorylated Rb allow DNA synthesis?(hyperphosphorylated)

A

Rb not attached to E2F (lower affinity)
Attract histone acetylase
DNA more loosely wound around histone (euchromatin)
so Transcription factors can access DNA for DNA synthesis

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40
Q

What are mitogens?

A

Extracellular signals that cells receive to stimulate cell division
Growth factors/cytokines
Causes cell to synthesis proteins to overcome restriction point

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41
Q

What is E2F?

A

Regulator that controls protein synthesis of proteins needed in S phase

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42
Q

What is the restriction point? (R point)

A

cellular brake that blocks cell from advancing from G1 phase to S phase

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43
Q

How do mitogens increase rate of cell division?

A

Bind to receptor tyrosine kinases (activation of RTK)
RTK is activated
Ras
MAPKs(RAF, MEK, ERK)
Myc gene codes for Myc
Myc stimulates E2F and cyclin D-CDK complex production
Activating genes promoting S phase

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44
Q

Different types of RAS

A

HRAS, NRAS, KRAS

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45
Q

What 2 pathways is Ras involved in?

A

MAPK pathway

p13 kinase pathway

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46
Q

MAPK pathway

A 
Ras is activated (GDP to GTP by GPRC)
Ras binds to Raf
RAF phosphorylates MEK
MEK phosphorylates ERK
ERK is activated
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47
Q

What can ERK do?

A 
Activates transcription factors to
Regulates:
proliferation
differentiation
Migration
inhibition of apoptosis
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48
Q

p13 kinase pathway

A 
Ras
p13 kinase
AKT
mTOR
Transcription of genes to increase cell proliferation
49
Q

What is MYC?

A

genes that code for transcription factors

Involved in DNA repair, cell cycle, apoptosis, transcription and translation

50
Q

What does Myc heterodimerize with?

A

Max

51
Q

What does complex Myc-Max do?

A

Bind to DNA and activate cell proliferation, transcription and apoptosis
activate expression of the growth-promoting proteins cyclin D and CDK4, E2F transcription factors that promote advance through early G1 end entry to S phase

52
Q

What is a disease that results in amplification of Myc?

A

Burkitt’s lymphoma

53
Q

Burkitt’s lymphoma

A

Translocation of chromosome 8 and 14
Causes coded region of MYC to bind to promoter
enhance production of igH= transgenic expression

54
Q

Neuroblastoma

A

Amplification of MYC

55
Q

Therapeutically interfering with MYC

A

OMOMYC= mutated version of MYC
interferes with target genes of MYC
can heterodimerize with max= OMOMAX
OMOMAX= shuts down transcription= decrease cell proliferation

56
Q

What is p14ARF?

A

alternate reading frame protein product of the CDKN2A locus -encodes a key activator-controls stability of the p53 tumor suppressor

57
Q

What is ARF?

A

Protein encoded by an exon upstream of the first INK4a exon

shares exons 2 and 3 with INK4a

58
Q

What can happen in mutations of p14ARF locus?

A

simultaneously inhibits Rb and p53 pathways

Epigenetic silencing by DNA hypermethylation= same effect.

59
Q

What are p16 and p15?

A

CDK4/6 inhibitors

60
Q

What is p21Cip1?

A

CDK inhibitor

61
Q

What is p21Cip1 encoded by?

A

CDKN1A

62
Q

What does p21Cip1 encode?

A

protein-belongs to the Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitor proteins

63
Q

Examples of p21Cip1

A

p27Kip1

p57Kip2

64
Q

What do p21Cip1 do?

A

encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes by obstructing the ATP-binding site in the catalytic cleft of the CDK.

65
Q

Why are INK4 and Cip/Kip proteins referred to as cell cycle inhibitors?

A

major function is to stop or slow down the cell division cycle by controlling cell cycle progression at G1

66
Q

What cellular functions does MYC control?

A

cell proliferation, cell adhesion, metabolism and protein biosynthesis

67
Q

What are TGFB receptors?

A

single pass (span the plasma membrane once) serine/threonine kinase receptors

68
Q

What does MYCMAX do?

A

Heterodimer
Activate expression of the growth-promoting proteins cyclin D and CDK4
and E2F transcription factors= promote advance through early G1 end entry to S phase

69
Q

What does MYC also work with?

A

Miz-1

70
Q

What do MYC and Miz-1 do?

A

Prevents expression of p15INK4B, p21Cip1, and p27Kip1 CDK inhibitors

71
Q

How does TGF-B team up with Miz-1

A

When smad2/3-smad4 heterotrimeric complex goes to nucleus
Teams up with Miz- 1 - activate the expression of p15INK4B and p21Cip1, and p27Kip1 CDK inhibitors to inhibit cell cycle progression.

72
Q

TBF Beta and MYC competition for Miz-1

A

TGF Beta outcompetes mYC
MYC levels collapse
so TGF Beta continues to promote CDK inhibitors

73
Q

Rb and p53 mutation

A

Greatly contribute to cancers

74
Q

What are Rb and p53 targeted by?

A

DNA tumour viruses

75
Q

Why do DNA tumour viruses target Rb and p53?

A

DNA tumour viruses express oncoproteins
Takes over host-cell DNA replication machinery in order to replicate their own genomes-this machinery is available in late G1 and S phases
Virus inactivate Rb as well as p107 and p130 (protein homologues of Rb)
causing infected, initially quiescent cells to enter S phase.

76
Q

What do cells that are infected by DNA tumour viruses try do in response to Rb inactivation?

A

activating their p53 alarm systems
= Direct response to the excessive activity of E2F transcription factors- results from the functional inactivation of Rb.
So viruses also need to inactivate the p53 response.

77
Q

What is human papillomavirus?

A

Creates 2 viral genes E6, E7

78
Q

What does the viral gene E7 do?

A

Binds to the Rb protein
Displaces the E2F transcription factors that are normally hidden by Rb
Promotes progression through the cell cycle

79
Q

What does viral gene E6 do?

A

Binds to and mediates the degradation of p53 and BAX (pro-apoptotic member of the BCL2 family)
Activates telomerase

80
Q

What are low risk strains of HPV?

A

1,2,4,7

Cause squamous papilloma (benign warts)

81
Q

What re high risk strains of HPV?

A

16,18

cervical cancer

82
Q

Difference between E6 and E7 of high risk and low risk strains

A

E6 and E7 of high risk train= higher affinity for their targets than that of low risk strains

83
Q

What’s HTLV-1?

A 
Human T-cell leukaemia virus-1 
Endemic in Japan and Caribbean 
Viral DNA integrates into host chromosome
Tax protein inactivates p53
and p16 
activates cyclin D 
increase in cell division
84
Q

What causes monoclonal T cell leukaemia/lymphoma?

A

1 proliferating T cell suffers additional mutations

85
Q

Structure of MYC

A

a bHLH/LZ (basic Helix-Loop-Helix / Leucine Zipper) transcription factor
MYC binds DNA via C-terminus bHLH domain
the LZ dimerizes with MAX, also a bHLH transcription factor
MYC recruits co-activators via N-terminus

86
Q

Examples of MYC being frequently translocated and amplified

A
  1. Translocation of MYC to igH locus= upregulation of MYC

2. MYC amplification in medulloblastoma and MYCN amplification in neuroblastoma

87
Q

What happens when Ras is mutated?

A

Production of permanently activated Ras proteins
Leads to continuously active pathways
even in absence of signalling molecule
Drives proliferation and survival

88
Q

Which cellular receptors activate Ras?

A

RTKs
GPCRs
These signaling cascades= initiate RAS activation by assembly of several scaffolding proteins=mediate the conversion of RAS from an inactive GDP-bound form to an active GTP-bound state

89
Q

How can Ras be further activated?

A

By additional Ras-GEFs (guanine exchange factor)
including RAS-GRF and RAS-GRP family members
GEFs allows inactive bound GDP ras to activated Ras bound to GTP

90
Q

How is Ras negatively modulated?

A

By a series of RAS-GTPase activating enzymes (RAS-GAPs)

These convert GTP to GDP and therefore inactivated Ras

91
Q

Example to show MYC-RAS are cooperating oncogenes

A

in mouse models of breast cancer, the presence of high levels of Myc expression AND constitutively active Ras signalling leads to a significantly higher incidence of cancer than is observed with EITHER high Myc expression OR constitutively active Ras signalling alone

92
Q

Role of p13K/ATK/mTOR pathway

A

controls multiple cellular processes- metabolism, motility, proliferation, growth, and survival
It is one of the most frequently dysregulated pathways in human cancers

93
Q

What factors activate proto-oncogenes?

A

PIK3CA, PIK3R1, AKT, MTOR

94
Q

What factors inactive tumour suppressor genes?

A

PTEN, TSC1, TSC2, LKB1

95
Q

What is a common feature of cancer?

A

Activation of proto-oncogenes

Inactivation of tumour suppressor genes

96
Q

What are tumours often dependent on?

A

Mutations in proto-oncogenes and tumour suppressor genes

In a study: inactivation of Myc or reactivation of p53= inhibited tumour growth

97
Q

What are serial biopsies?

A

important tool in understanding disease and guiding treatment
Detect organ confined cancers

98
Q

What play an important role in understanding disease and pre-clinical development of therapies?

A

Animal models

99
Q

What are the significant drawbacks of chemotherapy?

A
  • has significant side effects- hair loss, nausea, and vomiting
  • It can lead to neutropenia – in serious cases, febrile neutropenia= can often be fatal.
  • It causes DNA damage to normal cells – can lead to secondary cancers.
  • Chemotherapy regimens can often be harsh – may be unsuitable for weakened patients, due either to age/pre-existing conditions.
  • Rates of recurrence can be high: vary widely between 9–100%
100
Q

What are targeted cancer therapies?

A

Drugs or other substances that block the growth and spread of cancer by interfering with specific molecules (“molecular targets”) that are involved in the growth, progression, and spread of cancer
Can also be called molecularly targeted therapies/drugs

101
Q

Differences between targeted therapy and chemotherapy

A
  1. Targeted- act on specific molecular targets that are associated with cancer but most standard chemotherapies act on all rapidly dividing normal and cancerous cells
  2. Targeted- are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells
  3. Targeted= cytostatic (they block tumor cell proliferation), but standard chemotherapy agents= cytotoxic (they kill tumor cells)
102
Q

What are the most actively explored targets for drugs?

A

Growth factor receptors and downstream non-receptor signaling

103
Q

What is BRAF?

A

Initiates cell proliferation
Human gene that codes for protein B-Raf
This gene= proto-oncogene
Part of RAS/MAPK pathway

104
Q

What are BRAF inhibitors?

A

These drugs attack BRAF directly

Slow down growth of tumours

105
Q

What are BRAF inhibitors used in?

A

in the 50% of patients with metastatic melanoma whose tumors harbor activating mutations
However, for the vast majority of patients, responses persist for less than a year

106
Q

What is a common feature of the vast majority of molecularly targeted drugs?

A

Eventual treatment failure

107
Q

An example of a BRAF inhibitor

A

Vemurafenib

108
Q

how do BRAF inhibitors work?

A

They prevent BRAF being converted to MEK in RAS/MAPK pathway (Ras,BRAF,MEK,ERK)

109
Q

What do the great majority of target drugs aim for?

A
  1. Inhibiting activity of a target enzyme
  2. Agonizing the activity of a target receptor (agonists mimic the action of the signal ligand by binding to and activating a receptor)
  3. Antagonizing the activity of a target receptor. (antagonists bind to a receptor without activating it, and decreases the receptor’s ability to be activated by other ligands)
110
Q

Graphs showing ligand conc-receptor and enzyme-substrate conc

A

Ligand conc(on x axis) Substrate conc (on x axis)
Occupancy of receptor (y axis) rate (y axis)
Both graphs increase then curve off
enzyme-substrate graph= reaches Vmax
Ligand-receptor graph= reaches Bmax

111
Q

Reasons for failure of molecularly targeted drug treatment

A
  1. Resistance to enzyme inhibitors because of of mutations in the substrate-binding domain of enzyme active site
  2. Resistance to agonists/antagonists due to of mutations in the ligand-binding domain of the receptor.
  3. Activating/deactivating mutations to other components of the signalling pathway that can compensate for inhibition/agonism/antagonism of the target
  4. Over/under-expression of other components of the signalling pathway that can compensate for inhibition/agonism/antagonism of the target
  5. The presence of alternative/parallel signalling pathways (redundancy) that allow the cell to bypass inhibition/antagonism of the target
  6. Using other protein family members to take the place of the target that is being inhibited/antagonised
112
Q

Summary

A
  • The vast majority of cancers=mutations to key proto-oncogenes and/or tumour suppressors=in cell proliferation and survival.
  • This will always involve, at least in part, the overcoming of cell cycle checkpoint controls.
  • Cytotoxic chemotherapy is and will for the foreseeable future remain a mainstay of cancer therapies but has significant drawbacks
  • Targeted cancer therapies hold great promise but have yet to fully realize their potential
113
Q

In the MAPK pathway what is the ligand and final regulatory protein?

A

Ligand= EGF= Epidermal growth factor (Binds to EGFR)

Final protein= ERK

114
Q

EGF binding to EGFR

A 
2 monomers (like RTK)
Causes dimerisation
due to autophosphorylation of tyrosines in intracellular part of receptor
115
Q

G1 checkpoint

A

checks for
nutrients
growth factors
DNA damage

116
Q

G2 checkpoint

A

Checks for
Cell size
DNA replication

117
Q

M checkpoint

A

Checks for

chromosome spindle attachment

118
Q

How does uncontrolled cell growth occur

A
  1. Activation of oncogenes- Myc and Ras

2. Inactivation of tumor suppressor genes- p53, APC, BRCA1/2

Cell signalling and proliferation (4 decks)

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