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BMS3 > Cancer Biology > Flashcards

Cancer Biology Flashcards

1
Q

The major risk factor of cancer is..

A

Age

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2
Q

The majority of cancers are … causing..

A

Benign. These only cause harm when they expand and press on organs, and if they release high levels of hormones (thyroid adenoma)

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3
Q

Metastases of tumours cause ..% of cancer deaths

A

90%

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4
Q

8 hallmarks of cancer are:

A
  1. sustained proliferative signalling
  2. evasion of growth suppressors
  3. Invasion and metastasis
  4. evasion of immune response
  5. genomic instability
  6. resisting cell death
  7. inducing angiogenesis
  8. replicative immortality
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5
Q

Most tumours arise from …

A

epithelial tissue

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6
Q

hyperplastic tissues have..

A

excessive cell numbers

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7
Q

metaplastic tissues have..

A

abnormal cell types in wrong locations

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8
Q

dysplastic tissues are..

A

abnormal in size and shape

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9
Q

neoplastic tissues..

A

grow and invade other tissues

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10
Q

tumours can be heterogeneous as..

A

cells can acquire a new mutant allele within a population of cells

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11
Q

Limitations of mice models are:

A

Characteristics of mice/human tumours may be different.
Cancers may behave differently.
Time of onset is different (age).

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12
Q

The first tumour virus discovered was … by what experiment

A

Rous sarcoma virus. RSV was taken, grounded and filtrated from chicken and inserted into another chicken, which developed sarcoma.

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13
Q

In culture, tumour cells show 2 features:

A

Anchorage independent growth - tumour cells grow in semi-solid medium whereas normal cells can’t.
Altered morphology - thicker, no contact inhibition and rounded cells.

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14
Q

V-src and C-src in RSV possessed different cellular properties:

A

v-src acts as a potent oncogene in infected chickens.

c-src acts as a proto-oncogene in uninfected chickens.

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15
Q

The experiment proving that viruses did not cause human cancer

A

Carcinogens were thought to activate latent endogenous viruses in humans. When human cells and viruses were mixed, clusters of infectious outbreaks and isolation of viral particles from tumours were expected to form and be observed. This did not happen; virus did not cause cancer.

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16
Q

Oncogenes were first detected in NIH 3T3 mice fibroblasts in this experiment

A

DNA from cancer cells was added to fibroblasts. If a transforming gene (oncogene) is present, it may be incorporated into the genome and create transformed loci in culture. When these foci are injected into another mouse it causes tumour formation.

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17
Q

Injecting transformed foci to induce tumour formation showed that the origin of cancer was..

A

Not from viral infection or activation of viral genome. It shows that oncogenes are of cellular origins.

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18
Q

The first oncogene discovered was

A

c-Ras

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19
Q

The c-Ras sequence was discovered through experiments using..

A

bacteria attached to DNA fragments. Fragments which produce foci are collected and DNA is extracted. Repeated mixing and extracting of DNA will eventually collect a sample only containing tagged fragment. This was then run on Southern blot.

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20
Q

H-Ras and K-Ras DNA probes were seen to also bind to oncogenes in…

A

human bladder and colon carcinoma.

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21
Q

Many cancers carry mutations in Ras genes: … with mutations in residues: …

A

H-Ras, N-Ras and K-Ras. Mutations are found in 3 specific codons, with substitutions in residues 12, 13 and 61.

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22
Q

PDGF is platelet derived growth factor, and is a stimulator of..

A

fibroblast proliferation

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23
Q

Oncoproteins dictate what of a cell

A

The growth-stimulating machinery of a cell. They can delude cells into thinking they have encountered growth factors.

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24
Q

To find out what kind of molecule src was, antibodies were produced first and src was incubated with… what happened?

A

ATP. Src became phosphorylated, suggesting it was a protein kinase.

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25
Q

What does a protein kinase do?

A

It is an enzyme which removes Pi from ATP and phosphorylates other protein substrates, affecting downstream targets of a pathway

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26
Q

Src phosphorylates which residue in particular, and how much does this contribute to the cell’s phosphoproteins.

A

Tyrosine residues. This is odd as phosphorylated tyrosine - phosphotyrosine only contributes to 0.05-0.1% of a cell’s phosphoamino acids.

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27
Q

Cells transformed by src had phosphoamino acids levels of 1%, unlike other oncogenes. This indicates that tyrosine phosphorylation..

A

is used in mitogenic signalling pathways - induces proliferation

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28
Q

Growth factor pathways activate..

A

kinases to phosphorylate tyrosines (and other proteins) to cause proliferation

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29
Q

EGF binds to EGFR. How does the EGFR function?

A

It can work as a ligand independent receptor, meaning signals can be sent without the binding of EGF. It does this as a truncated receptor (monomerically).

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30
Q

How does EGFR function as a dimeric receptor?

A

Cytoplasmic domains of each unit phosphorylate each other - transphosphorylation

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31
Q

In cancer, EGFRs are..

A

overexpressed. Monomers move in the membrane and collide frequently, transphosphorylate, and emit growth signal

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32
Q

The discovery of EGF was done with purified growth factors and HeLa cancer cells..

A

EGF was on a solid and porous support and cancer cells were run through it in a column. The column was eluted and one protein was found - it had a similar sequence to src. This was similar to tyrosine kinase.

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33
Q

Ras acts as a binding protein for..

A

guanine and GTPase

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34
Q

The function of Ras was proven by what experiment using radioactivity

A

Radioactive displacement - a radioactive immunoprecipitate of GDP and Ras was mixed with other non-radioactive compounds to see if they would competitively bind to Ras. GDP and GTP bound.

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35
Q

An experiment using bacteria to show Ras function

A

2 groups of bacteria, 1 expressing cRas and 1 with a mutant Ras (HaRas) were incubated with radioactive GTP. Chromatography of cRas bacteria showed increasing amounts of GDP with time, unlike the mutant. Shows Ras is a GTPase.

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36
Q

Studies of Drosophila sevenless mutants and C. Elegans Let23 mutants discovered..

A

Enhancers and suppressors of a pathway (by epistatic analysis). Sequences showed similarities to growth factors, EGFRs, tyrosine kinases and Ras.

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37
Q

How was the gene in between tyrosine kinase and Ras found?

A

Genomic fragments were plated out and fluorescent tyrosine kinases were added and washed off. Colonies bind and DNA is extracted. This found GRB2 - homologous to SEM5 (Drosophila).

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38
Q

Ras is involved in multiple pathways, if one of …. components is affected, the whole pathway is altered.

A

3 components: Ras, GRB2 and tyrosine kinases

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39
Q

Oncogenic Ras differs from normal Ras by..

A

A singular base change - Glycine = proto-oncogene, Valine = oncogene

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40
Q

Most cancers show … effects unlike viral oncogenes….

A

recessive effects. Viral oncogenes show dominant effects.

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41
Q

To determine whether cancers are dominant or recessive, what was used

A

Sendai virus was used to fuse cancer cells with normal cells; all DNA in one nucleus. When fused cells were transplanted in xenograft mice, a recessive phenotype was seen, suggesting something was repressing cancer

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42
Q

Retinoblastoma is what kind of cancer

A

Eye. It can be sporadic or familial, usually unilateral. Only familial genes have bilateral retinoblastoma.

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43
Q

How was the recessive nature of the Rb gene studied

A

Knudson’s 2 hit hypothesis on a semilog graph; shows that there are 2 determinants for unilateral, but only 1 for bilateral. Familial already has ‘one hit’ present whereas sporadic cases need ‘2 hits’.

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44
Q

ReFLP is used to

A

find loss of heterozygosity and loss of tumour suppressor genes. EcoR1 will not cleave if mutated, creating different fragment lengths.

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45
Q

Synthetic lethality is when..

A

If 2 specific mutations are present together, cells result in death

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46
Q

Synthetic lethality has been used in cancers with what mutations and with what therapies

A

BRCA mutated genes (ds break repair) - PARP inhibitors
MSH1/2 (mismatch repair) - Pol beta, DNA polymerase
VHL (tumour distrib patterns) - kinase inhibition (CDK6, MET and MAP2K1)

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47
Q

4 important experiments of the cell cycle show us:

A

phase lengths
no/ of cells
how cycle is controlled
proteins needed

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48
Q

Cell cycle is good to visualise in Drosophila because..

A

They have a very fast cell cycle which is in syncytium

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49
Q

The length of cell cycle phases are calculated by..

A

Using radioactive phosphate to be incorporated into DNA backbone during replication. % of phosphate multiplied by doubling time = phase length

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50
Q

How long is doubling time in mammalian cells

A

22 hours

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51
Q

FACS is ..

A

fluorescent activated cell sorting

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52
Q

FACS can tell us … about the cell cycle and how

A

How many cells are in each phase. Cell are passed through a narrow path with lasers which detect the size and amount of DNA in a cell (by wavelength of light emitted).

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53
Q

FACS can be more accurate if done..

A

in 3D and bivariately. This takes density into account, making results more accurate.

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54
Q

How was control of the cell cycle discovered?

A

Through budding and fission yeast. Mutants of cell cycle were studied by using temperature sensitive mutant, arresting cells at certain points of the cycle. Genes were discovered by re-introducing them through plasmids

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55
Q

Cell cycle phase is easy to identify in yeast because..

A

Phases have morphological features: a bud forms in S phase in budding yeast

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56
Q

Using frogs identified proteins needed in cell cycle. How?

A

Centrifugation and extraction of concentrated frog cell cytoplasm was used to add DNA fragments to. Nuclei form around fragments and cell cycle can be observed in culture

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57
Q

Cells in any stage of interphase will enter mitosis in the presence of mitosis factors. This was discovered in 2 experiments:

A

Fusing interphase and mitosis cells with Sendai virus.

Injecting cytoplasm from a mature oocyte into another induced mitosis.

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58
Q

M-phase is induced by..

A

histone 1 kinase activity

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59
Q

Cell division is activated by..

A

cyclically synthesised proteins (cyclins)

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60
Q

The first studies of cyclically synthesised proteins was done in..

A

Yeast. Wee1 and cdc25 mutants were studied, and similar genes were screened for in mammals.

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61
Q

What are cyclins? (3 points)

A

They are proteins which are differentially expressed.
They allow transition into the next phase.
They bind to specific CDKs to be activated.

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62
Q

M phase is driven by which cyclin and CDK?

A

Cyclin B and CDK1

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63
Q

Cyclin A and CDK1/2 drives which cell cycle phase?

A

S phase

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64
Q

Which cyclin and CDK drive G1 phase of cell cycle?

A

Cyclin D and CDK4/6

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65
Q

G1/S is driven by cyclin and CDK..

A

Cyclin E and CDK2/1

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66
Q

How does CDK1 differ from other CDKs?

A

It is essential for cell division in the early embryo

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67
Q

What regulates CDK activity?

A

Activators are cyclins and inhibitors are CKIs. Activation is dependent of phosphorylation of threonine residues on T loops (activation loops) by CAKs (CDK activating kinase). There is also inhibitory phosphorylation.

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68
Q

CKIs such as ….. are produced in response to..

A

p57, p27 and p21 are produced in response to anti-proliferative signals

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69
Q

Growth factors control cycle partially through..

A

regulation of CKI function

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70
Q

How does Rb function in the nucleus?

A

Without mitogens, Rb is a DNA binding protein which inactivates E2F. This inhibits transcription of S phase genes. All downstream genes are turned off to prevent cell proliferation.

71
Q

Growth factors upregulate cyclin D to control Rb, how?

A

Cyclin D directly phosphorylates Rb so it cannot bind to E2F, removing inhibition of transcription of downstream genes.

72
Q

Papova virus SV40 was used to transform human cells. DNA replication was induced by…and was discovered by..

A

viral protein Polyoma Large T - identified through immunoprecipitation using antibodies and radioactive methionine.

73
Q

Experiments with oncogenic Ras and p53 showed that..

A

Wildtype p53 suppressed the transformed phenotype produced by Ras, indicating p53 is a tumour suppressor.

74
Q

Double knockout mice of p53 showed..

A

that deletion of p53 showed decreased survival but did not induce embryonic lethality. This does not follow Knudsen’s rule.

75
Q

Monoclonal antibodies of p53 were used to study p53 structure by..

A

Mapping where antibodies bound to locate the binding site. Truncated mutations were used.

76
Q

Monoclonal antibodies were also used to look at p53 expression, what was seen?

A

p53 has a short half life of 20 minutes.

77
Q

p53 antibodies were added to cells transformed by Polyoma Large T. What was seen and what does it suggest?

A

When Large T was present, there was reduced staining for p53, even though the same amount of p53 was present. Suggests there are different conformations of p53.

78
Q

Mutations of p53 are mainly..

A

missense - substitution mutations (75%)

79
Q

Sucrose density centrifugation showed p53 to have what structure?

A

tetrameric, needing 4 functional subunits

80
Q

A heterozygous mutant of p53 would not function, why?

A

All 4 subunits are needed for p53 to function. Any mutations causes a dominant negative effect.

81
Q

p53 looks after chromosomal integrity, stabilising when there are cancer-causing factors of:

A

UV radiation, block of transcription, hypoxia, lack of nucleotides and oncogenic signalling.

82
Q

Target genes of p53 were found by re-introducing them into a null cell line by… what genes were found and how?

A

Dexamethazone. Subtractive hybridisation identified WAF1.

83
Q

What is WAF1 and what is it targeted by?

A

WAF1 is a CKI; p21. This binds to CDKs and directly inhibits them, arresting cell cycle.

84
Q

downstream genes of p53 are involved in (4):

A

cell cycle arrest, DNA repair, blockage of angiogenesis and apoptosis

85
Q

p53 levels are controlled by a pathway. Loss of any component lead to dysregulation of cellular response to stress. Components are (5):

A

Ras produces E2F.
E2F activates ARF.
ARF sequests MDM2 in the nucleolus.
MDM2 tags p53 with ubiquitin.

86
Q

Re-activation of p53 is a possible treatment of cancer. Work by..

A

mimicking p53 activators

87
Q

Protein kinases ATM and ATR are produced in response to genomic stress. What do they do to p53 and what occurs because of this?

A

The phosphorylate p53 to prevent apoptosis. This will allow p53 to induce stress responses such as ds DNA break repair.

88
Q

A mutator phenotype is characterised by.. (2)

A

Gross chromosomal instability.

Increased amount of mutations.

89
Q

Checkpoint of cell cycle and extrinsic pathways which..

A

makes sure events of the cycle are dependable on each other.

90
Q

Checkpoint genes and homologues were identified when..

A

studying yeast and synthetic lethality.

91
Q

Genomic instability occurs in the sensitive phases of the cell cycle..

A

S and M, before DNA is replicated.

92
Q

Carcinomas are dependent on the order of mutations. The earliest and most common mutation…

A

are driver mutations.

93
Q

Instability occurs once every ….. in normal cells. In tumour cells..

A

once every 10 million divisions. In cancer this can be thousands of times higher.

94
Q

Instability comes in 2 forms:

A

Chromosomal inst. (CIN).

Microsatellite inst. (MIN).

95
Q

What is chromosomal instability?

A

Growth changes in chromosomes - rearrangements, LOH, aneuploidy and amplification.

96
Q

Microsatellite instability is..

A

point mutations (sub, ins, del) in long regions of repeated bases.

97
Q

Cells defend themselves by..(6) Mutations in this pathways push cells towards mutator phenotype

A 
Proof reading before replication - DNA polymerases.
Mismatch repair.
Homologous recombination.
dsDNA break repair.
Base excision.
Nucleotide excision repair.
98
Q

Checkpoint mutations in yeast are..

A

RAD9 and Cdc9 together - synthetic lethality

99
Q

When RAD9 and Cdc9 mutation are under restrictive temperatures..

A

Cell arrests in G2. However when the mutations are together, viability is lost and there is no recovery from arrest.

100
Q

Mitosis is dependent on completion of … which can be surpassed by…

A

S phase. Caffeine can lead to catastrophic mitosis

101
Q

ATR and ATM are … and are transducers of..

A

Protein kinases which transduce a response to DNA damage

102
Q

ATM and ATR phosphorylate … which acts on …

A

Chk1 is phosphorylated and acts on Wee1 and Cdc25 to activate or inactive Cdk1

103
Q

Replication stress is detected by..

A

ssDNA on replication forks.

104
Q

Mutations of checkpoints can be targets of therapeutics as..

A

a response to damage can be induced. Chemotherapy can kill cancer cells by disrupting more checkpoints.

105
Q

Cancers metastasise by..

A

invasion-metastasis cascade

106
Q

The probability of all steps of the invasion-metastasis cascade being completed is very low. This is called..

A

Metastatic inefficiency

107
Q

Localised invasion starts when cancer breaches..

A

the basement membrane and invades nearby stroma.

108
Q

When cancer cells migrate, they need to change their phenotype. Why?

A

Epithelial cell organisation is incompatible for motility.

109
Q

tumour epithelial cells transition to..

A

mesenchymal cells

110
Q

EMT involves losses of certain properties: (5)

A 
cytokeratin
tight junctions
E-cadherin junctions
cell polarity
factors expressed
111
Q

EMT involves acquisition of: (5)

A 
fibroblast shape
motility
invasiveness
fibronectin
protease
112
Q

Cancer cells enter blood vessels via..

A

intravasation

113
Q

Intravasation occurs as cancer cells interact with..

A

macrophages and endothelial cells to enter the capillary lumen

114
Q

Blood is a hostile environment meaning..

A

only a small proportion of tumours can found metastatic colonies

115
Q

Cancer cells exit vessels by..

A

extravasation

116
Q

The most difficult step of the IMcascade is forming new micrometastases and macrometastases. Why?

A

The environment of foreign surrounding tissue does not provide support.

117
Q

Different modes of migration are:

A

Collective cell

Single cell

118
Q

Cells show plasticity by switching between different modes of migration in order to..

A

stay motile. This makes designing anti-metastatic therapies difficult.

119
Q

Single cell migration is..

A

when cells lack cell-cell interactions and exhibit amoeboid-like and mesenchymal-like phenotypes

120
Q

Collective cell migration is when..

A

cells maintain cell-cell adhesions. They move as narrow linear strands with leader cells acquiring mesenchymal characteristics.

121
Q

p53 opposes EMT by..

A

inhibiting loss of cell-cell junctions.

inhibiting pro-migratory proteins.

122
Q

p53 mutations in cancer affect incidence of metastases. Mutant p53 promotes..

A

recycling of integrins and growth factors from endosomes to the plasma membrane. This sustains AKT signalling, promoting invasion.

123
Q

The immune system first responds to cancer cells by..

A

innate response - neutrophils, macrophages and NK cells

124
Q

Tumour cells avoid immune recognition by: (4)

A

low immunogenicity - express no antigens for MHC complexes to bind to.
Express endogenous antigens.
Secrete TGFb or IL-10 to suppress immune cells.
Secrete factors to create a barrier around the tumour.

125
Q

What are tumour-associated macrophages (TAMs)

A

They are macrophages in the tumour microenvironment which promote tumour growth, angiogenesis and suppress T cells. They can make up 50-80% of a tumour.

126
Q

TAMs are found in hypoxic areas and express..

A

Arg1, IL-10 and TGFb

127
Q

Anti-tumour macrophages express..

A

NOS, IL-1 and IL-12 and TNFa

128
Q

Immunotherapies today include: (5)

A

Monoclonal antibodies - to recognise cancer cells.
Immune checkpoint inhibitors - so cancer cells are not seen as endogenous.
Vaccines.
Adoptive cell transfer - gene editing.
Cytokines - boosts immune system but very complex.

129
Q

Cell based therapies involve..

A

targeting tumour cells and delivering therapeutic drugs.

130
Q

Trojan Horse was a treatment consisting of macrophages with..

A

cancer-killing viruses inside them. This allowed them to travel deep into tumours.

131
Q

Trojan Horse was used in combination with Docetaxel (chemo) in..

A

nude mice to target the prostate. Re-growth of tumours improved but still needed to be looked at in clinical trials.

132
Q

Other approaches to targeted therapies include..

A

magnetic macrophage technology: a magnetic field is applied near the tumour to increase specificity.

133
Q

Epigenetic processes affected in cancer…

A

acetylation, methylation and phosphorylation of core histones

134
Q

Alterations of chromatin structure affects…

A

gene transcription and accessibility of target genes

135
Q

Histones are covalently modified at their..

A

N terminal tails

136
Q

Acetylation occurs on … residues

A

lysine

137
Q

Methylation occurs on … residues

A

lysine and arginine

138
Q

phosphorylation of histone tail H3 occurs on … residues

A

serine 10

139
Q

Enzymes adding acetyl or methyl groups are..

A 
Histone methyltransferases (HMTs)
Histone acetyltransferases (HATs)
140
Q

Acetylation of histones creates binding sites for…

A

transcriptional activators containing bromodomains

141
Q

Methylation of histones creates binding sites for…

A

Transcriptional activators containing PHD Zn finger domains (H3K4).
Repressors containing chromodomains (H3K27)

142
Q

EZH2 is a Polycomb gene which encodes H3K27. Without this gene…

A

chromatin is ubiquitously active; genes are over-expressed.

143
Q

Mutant EZH2 protein is found in cancer. It has been targeted and blocked by..

A

selective inhibitors - only target mutant form.

144
Q

Point mutations which catalyse trimethylation of H3K27 are highly associated with..

A

non-Hodgkins lymphoma

145
Q

Chromosomal translocations which occur in HAT or HMT genes can cause..

A

Leukaemia

146
Q

Identifying susceptibility genes helps understand..(4)

A

Disease mechanism
Drug targets
Identify people at risk
Drug response

147
Q

Tumour suppressor gene mutations are seen in familial cancers such as..

A 
Adenomatous polyposis - APC
Colon cancer - MLH1, MSH2
Breast cancer - BRCA1/2
Li-Fraumeni - tp53
Gorlin's - PTC
Ataxia telangiectasia - ATM
Retinoblastoma - Rb
Melanoma - CDKN2A
148
Q

Familial genes have been identified through:

A

Positional cloning - linkage analysis followed by cloning and sequencing. If the disease co-segregates with markers, the region is fine-mapped for mutations. It achieves a LOD score - how likely the disease and marker are linked

149
Q

ATM phosphorylates MRE11 and NBS1 in order to..

A

initiate DNA repair

150
Q

The MRE11/NBS1/RAD50 complex is associated with..

A

BRCA1 and other breast cancers

151
Q

Leukaemias are classified by..

A

the cell lineage of haemopoietic stem cells cancer has derived from

152
Q

Leukaemia is caused by a block of … causing …

A

Blocked maturation of immune system, causing over proliferation of immature cells to compensate

153
Q

Lymphoid leukaemias are … and affect …

A

ALL
CLL
MM
Affects B and T lymphocytes and plasma cells.

154
Q

Myeloid leukaemias are more common and involve more cell types such as:

A

granulocytes, platelts, monocytes and RBCs.

155
Q

Cytogenetics is..

A

study of genetics at the chromosome level by karyotyping (Gband staining)

156
Q

Cytogenetic features seen in leukaemia are:

A

deletion of monosomy of chromosomal material.

duplication, amplification of trisomy of chromosomes.

157
Q

Relocation of chromosomal material causes leukaemia in 2 ways:

A

Hybrid genes are formed producing a chimeric protein - increased tyrosine kinase activity and neoplastic growth.
Deregulating a gene through regulation of another gene - changes transcription and causes neoplastic growth.

158
Q

Strategies to target cancer include:

A

discourage proliferative and anti-apoptotic signalling

promote apoptotic signalling

159
Q

Indolent tumours have..

A

low invasive and metastatic potential. No point of treatment

160
Q

Criteria of tumours being aggressive are:

A

Age
Size of tumour
No. of axillary lymph nodes affected (breast)
Histology and pathological grading
Receptor status (for growth factors acting as oncogenes eg. oestrogen)

161
Q

Cancer needs to be classified into subgroups with distinct properties so that it is not..

A

over treated

162
Q

Prognoses genes and signatures show different..

A

survival patterns

163
Q

In subtypes of myeloma, the NF kappa beta pathway is activated and can be targeted by I kappa beta inhibitor. Detecting this mutation tells us..

A

Myelomas without this mutation will show limited response to this treatment.

164
Q

In acute pro-myelocytic leukaemia, a pathway using RA and RAr differentiates myelocytes into neutrophils is mutated by..

A

chromosomal rearrangements. RAR gene translocates into the PML gene

165
Q

Using trans RA, a derivative of RA in acute pro-myelocytic leukaemia destroys mutant RA. How?

A

Trans RA recruits a specific ubiquitin ligase which only destroys RAr translocated in the PML gene. Leaves WT genes unaffected

166
Q

Cancers have poor checkpoint responses meaning they have no delay in cell cycle. Doxorubicin targets cancer cells by..

A

Causing normal cells to arrest in cell cycle. Cancer cells will not arrest and will produce fragmented nuclei which can be selected for by therapeutics.

167
Q

Why is it difficult to enhance apoptotic signalling in cancer?

A

Tumour suppressor genes would need to be targeted however they are missing in cancer. Most drugs inhibit biochemical functions rather than enhance them.

168
Q

Drugs which promote mutated p53 are: (2)

A

PRIMA1

Nutlin2

169
Q

PRIMA1 enhances p53 by..

A

covalently binding the the p53 core to resemble WT, reactivating the mutant

170
Q

Nutlin2 enhances p53 by..

A

targeting and preventing MDM2 from binding to p53. Preventing this complex will prevent apoptosis of p53, promoting p53 activity and apoptosis of cancer

171
Q

How would upregulation of p27 affect cancer?

A

p27 is a CKI. Upregulation would cause inhibition of Cdks, blocking proliferation. Seen in ovarian cancer

172
Q

Why are kinases effective drug targets? (3)

A

Many kinases act as oncogenes.
There are 518 in the genome.
They are ‘druggable’ - they have ATP binding sites which can be targeted.

173
Q

Tarceva (Erlotinib) targets the ATP binding site of..

A

EGFR

174
Q

High throughput screens can find drugs to inhibit kinases…how..

A

Large amounts of purified kinase is made through bacteria and is used to screen a large compound library. Hits which inhibit the kinase are studied and their structures are improved.

BMS3 (6 decks)

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