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Cancer Lectures > Cytoskeleton and Cancer > Flashcards

Cytoskeleton and Cancer Flashcards

1
Q

What is the cytoskeleton made up of?

A

Microtubules
Intermediate filaments
Actin microfilaments

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2
Q

Metastases are the end products of the invasion-metastasis cascade, true or false?

A

True

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3
Q

What is the efficiency of the invasion-metastasis cascade?

A

1 cell out of 5000, i.e. inefficient

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4
Q

What is the cytoskeleton?

A

A cellular inner framework that enables cells to move, change shape and much more

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5
Q

What is the diameter of microtubules?

A

25nm

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6
Q

What is the diameter of intermediate filaments?

A

10nm

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7
Q

What is the diameter of microfilaments?

A

8nm

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8
Q

Where are microtubules found?

A

They are present in the cytoplasm of all eukaryotic cells

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9
Q

What do microtubules exist as?

A

Long, rigid polymeric structures with a length between 200nm and 25um

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10
Q

What is the function of the microtubules?

A

To support cell structure and shape

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11
Q

What is the role of microtubules in the movement of structures within the cell?

A

Serve as a conveyor belt for moving organelles and secretory vesicles throughout the cytoplasm

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12
Q

What is the role of the microtubules in mitosis?

A

They form spindles during mitosis

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13
Q

What are microtubules a major component of?

A

Cilia and flagella for specialised surfaced structures, e.g. of epithelial cells of air passage lining

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14
Q

At the centrosome-microtubule junction, what are the nucleating sites formed of?

A

Rings of gamma-tubulin

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15
Q

What type of filament are microtubules that are growing from the centrosome?

A

Polar filaments (- to +)

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16
Q

What is the catastrophe and rescue theory?

A

That microtubules have a reverse switch from growth (polymerisations) to shrinking (depolymerisation) and vice versa

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17
Q

Define treadmilling

A

A process of dynamic instability on both + and - ends of the polymer

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18
Q

Is treadmilling of microtubules present in vitro or in vivo or both?

A

It is present in vitro and partially in vivo

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19
Q

Are all minus ends of the microtubules bound to the centrosome?

A

Not all minus ends

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20
Q

What are microtubules stabilised by?

A

Microtubule associated proteins (MAPs)

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21
Q

What do MAPs do?

A

Bind mostly at the + end of microtubules and promote growth and disassembly

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22
Q

What are neurons stabilised by?

A

Tau, that binds to the sides of filaments and crosslinks adjacent microtubules

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23
Q

What MAP stabilises the leading tip of migrating cells (cell polarisation)?

A

‘Plus’ TIP proteins (+TIP), e.g. XMAP214 family, EBs

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24
Q

What is the function of kinesin 4/8?

A

Cargo translocation to + end

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25
Q

What is the function of kinesin 7/10?

A

Filament growth

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26
Q

What is the function of kinesin 8/13/14?

A

Promotes catastrophe

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27
Q

Post-translational modifications can modulate microtubule dynamics and and functions, true or false?

A

True

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28
Q

What post-translational modifications can control protein-protein interactions and microtubule dynamics?

A

Detyrosination and tyrosination (C-terminal Tyr)
Acetylation and deacetylation (Lys40)
Polyamination

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29
Q

What happens during prometaphase?

A

Chromosomes are condensed; microtubules interact with chromosomes

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30
Q

What happens during early metaphase?

A

Chromosomes form a metaphase plate

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31
Q

What happens during anaphase?

A

Duplicated chromosomes move to spindle poles

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32
Q

What happens during telophase?

A

Cell division to form two daughter cells

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33
Q

How does the drug paclitaxel affect mitosis?

A

Chromosomes don’t congress to the metaphase plate

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34
Q

How does the drug vinflunine affect mitosis?

A

Chromosomes remain at the spindle poles

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35
Q

Microtubules cannot be targeted by anticancer drugs, true or false?

A

False, they can be a target for anticancer drugs

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36
Q

Give examples of tubulin polymerisation inhibitors and their mode of action

A

Vinblastine: blocks + end
Colchicine: interacts with alpha tubulin heterodimer

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37
Q

Give an example of a tubulin depolymerisation inhibitor and its mode of action

A

Paclitaxel: suppresses dynamics

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38
Q

Can kinesins be potential targets for cancer drug development?

A

Yes

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39
Q

What is MMP1 and what is its function?

A

M-phase phosphoprotein 1

Controls cytokinesis

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40
Q

What is the function of EG5 kinesin?

A

Essential for bipolar spindle formation

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41
Q

What is CENPE and what is its function?

A

Centromere-associated protein E
Controls progression from metaphase to anaphase
Depletion initiates chromosomal instability

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42
Q

At what stage of clinical trials is the EG5 kinesis targeting drug ARRY-520?

A

Phase II trials in multiple myeloma

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43
Q

At what stage of clinical trials is the EG5 kinesis targeting drug LY2523355?

A

Phase II trials for 8 different solid tumours

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44
Q

What are intermediate filaments important for?

A

The mechanical stability of cells

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45
Q

Intermediate filaments belong to a small protein family encoded by ~20 different genes, true or false?

A

False, they belong to a large protein family encoded by ~70 different genes

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46
Q

How many types of intermediate filaments are there and what are these types based on?

A

6 types

Based on the primary sequence and structure

47
Q

Give an example of a type I intermediate filament

A

Epithelial keratins (acidic)

48
Q

Give an example of a type II intermediate filament

A

Hair keratins (basic)

49
Q

Give examples of type III intermediate filaments

A

Vimentin
Desmin (muscle cells)
Peripherin (peripheral neurons)
Glial fibrillary acetic protein (astrocytes)

50
Q

Give examples of type IV intermediate filaments

A

Internexin
Synemin
Syncolin
Neurofilaments

51
Q

Give an example of a type V intermediate filament

A

Nuclear lamins

52
Q

Give an example of a type VI intermediate filament

A

Nestin

53
Q

What is the diameter of intermediate filament polymers?

A

10nm

54
Q

Are intermediate filaments more or less dynamic than microtubules? Why?

A

Less dynamic, no turnover of subunits

55
Q

What regulates intermediate filament motility?

A

Microtubule-associated proteins

56
Q

What does a switch in the pattern of intermediate filaments suggest?

A

Epithelial to mesenchymal transition

57
Q

What is vimentin a marker for?

A

Epithelial to mesenchymal transition

58
Q

Are keratins diagnostic or prognostic markers in tumour pathology?

A

Both

59
Q

Is vimentin a diagnostic or prognostic marker in tumour pathology?

A

Prognostic

60
Q

What makes up the actin cytoskeleton?

A

Microfilaments

61
Q

What makes up microfilaments?

A

Actin filaments

62
Q

How can microfilaments be structured?

A 
As 2 strands of F (filamentous)-actin
As G (globular)-actin
63
Q

Where can alpha actin be found?

A

In muscle specific isoforms

64
Q

Where can beta actin be found?

A

In the cell cortex, in the leading edge of migrating cells

65
Q

Where can gamma actin be found?

A

In stress fibres

66
Q

What is located in the centre of G-actin?

A

ATP

67
Q

What is located in the centre of F-actin?

A

ADP

68
Q

Define actin treadmillg

A

The rapid turnover of actin filaments

69
Q

Is there the same or different kinetics of subunit binding and dissociation at the opposite ends of F-actin?

A

Different

70
Q

How does recycling of actin filaments occur?

A

Severing proteins and cofilins intercalate and cause actin monomer dissociation

71
Q

Do actin filaments treadmill in membrane protrusions?

A

Yes

72
Q

How does the capping and polymerisation of actin filaments work?

A

Capping proteins (formin, gelsolin, villin) deliver actin monomers to nucleation centres

73
Q

How does the branching of the Arp2/3 complex in actin filaments work?

A

Branching protein Arp2/3 intercalates between individual actin filaments

74
Q

What proteins are able to cross-link actin filaments to form thicker bundles or meshwork of higher mechanical strength?

A

Alpha-actinin
Fascin
Filamin
Tropomyosin

75
Q

How many coiled-coil tropomyosin proteins exist in mammals?

A

More than 40

76
Q

What do tropomyosin proteins exist as?

A

Coiled-coil parallel dimers that forma head-to-tail polymer

77
Q

What do tropomyosin proteins regulate?

A

Interactions of actin filaments with actin-binding proteins

78
Q

What do tropomyosin proteins control?

A

The stability of the microfilaments

79
Q

The actin cytoskeleton is a potentially vulnerable property of cancer cells, so why aren’t current inhibitors successful?

A

Unacceptable toxicity

80
Q

What is Tm5NM1/2?

A

An integral component of the specialised actin cytoskeleton of tumour cells

81
Q

What does the anti-tropomyosin compound TR100 disrupt?

A

The actin cytoskeleton

82
Q

Why has TR100 had such sensational success in clinical trials?

A

Because it does not compromise cardiac function

83
Q

What are myosins?

A

A superfamily of actin-based motor proteins

84
Q

How do myosins work?

A

They convert chemical energy in the form of ATP to mechanical energy

85
Q

What domains do myosins have?

A

A highly conserved globular head domain containing the actin-binding and ATPase domain
A neck domain to which light chains bind
A variety of functionally specialised C-terminal tail regions

86
Q

Outline the ‘power stroke’ mechanism for myosin movement along actin filaments

A
  1. Rigor state position
  2. ATP binding releases the actin filament
  3. ATP hydrolysis causes a shift in the ‘lever arm’ position
  4. Release of Pi
  5. Power stroke
  6. ADP is released
87
Q

During each power stroke cycle, how many molecules of ATP are hydrolysed?

A

One

88
Q

During each power stroke cycle, how far does myosin move?

A

5-25nm

89
Q

Describe the structure of myosin II

A

It is a hexameric protein consisting of three pairs of pepetides: two heavy chains, two essential light chains, and two regulatory chains

90
Q

What is the function of the coiled-coil domain in myosin II?

A

It is involved in the assembly of myosin II molecules into filaments

91
Q

Where is myosin II found?

A

In skeletal muscle, smooth muscle, and there can be non-muscle myosin

92
Q

What does myosin II have fundamental roles in?

A

Processes requiring reshaping and movement, e.g. cell adhesion, cell migration and cell division

93
Q

What is myosin II’s function dependent on?

A

Its ability to form bipolar filaments

94
Q

Myosin II filaments bind to actin through what?

A

Their head domains

95
Q

What does myosin II use in order to form filaments to regulate the cytoskeleton?

A

Its actin cross-linking and contractile functions

96
Q

How does the light chain of myosin II regulate its assembly?

A

It exists in a folded, assembly-incompetent form (10S)

Phosphorylation of the regulatory light chain on Ser19/Thr18 leads to an unfolded, assembly-competent form (6S)

97
Q

What does S100A4 do?

A

It binds to the C-terminus of myosin IIA and has been shown to inhibit the formation of myosin into filaments

98
Q

What are the two phosphorylation sites on myosin IIA that may play a role in S100A4 binding and/or filament formation?

A

S1916-PKC and S1943-CKII

99
Q

What does knockdown of S100A4 promote?

A

The formation of myosin IIA filaments

100
Q

What is actomyosin contractility controlled by?

A

Rho GTPase

101
Q

What is RhoGTPase?

A

A molecular switch that cycles between GDP and GTP bound states
It activates and interacts with downstream effectors

102
Q

Give some examples of Rho GTPases and where they can be found

A

Rac in lamellipodia
Cdc42 in filopodia
Rho in stress fibres
In focal adhesions

103
Q

How does a new focal adhesion form?

A
  1. Formation of focal complex
  2. Formation of stress fibres
  3. Growth of stress fibres
104
Q

What is cell migration needed for in the body?

A

Embryonic development
Wound healing in epithelial cells
To get white blood cells to the sites of infection
In fibroblasts to maintain the extracellular matrix
To allow the migratio of cancer cells to new sites in the body (cancer spreading/metastasis)

105
Q

What are the four stages of mesenchymal migration (in order)?

A

Protrusion, adhesion, translocation, retraction

106
Q

What happens to the migration of a amoeboid cell with no intrinsic polarity?

A

It will extend towards chemical and haptotactic stimuli

107
Q

Define chemotaxis

A

The directional cell movement towards an increasing concentration of a soluble factor (chemokines), contact with extracellular matrix ligands, or physical contact with other cells

108
Q

What is amoeboid migration based on?

A

The membrane blebbing along the cell surface, which is under control of actin polymerisation

109
Q

What are cortical actin dynamics controlled by?

A

Small GTPases

110
Q

What is the squeezing of round cells in the extracellular matrix (independent of extracellular matrix cleavage) a characteristic of?

A

Non-neoplastic cells (lymphocytes and neutrophils), or of tumour lymphoma and small-cell lung carcinoma cells

111
Q

What do short-lived and relatively weak interactions of the cell with the substrate (integrin-independent migration) mimic features of?

A

The single cell behaviour of the amoeba Dictyostelium discoideum

112
Q

What do carcinoma cells move along?

A

Extracellular matrix fibres and do not seem to be constrained by the matrix networks

113
Q

What are the three transitions in the mode of cancer cell migration?

A

EMT, MAT, CAT

Cancer Lectures (24 decks)

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