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Cellular and Molecular pathology > 8. Oncogenes > Flashcards

8. Oncogenes Flashcards

1
Q

what experiment proved that cancer can possibly be transmissible?

A
  1. a chicken from Rhode island had a lump
  2. took his chicken to a scientist
  3. the sarcoma was removed and broken up and filter
  4. inject this into a young chicken
  5. the chicken developed sarcoma
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2
Q

what is the lifecycle of a retrovirus?

A
  1. the virus in introduced into the cell
  2. use reverse transcriptase to make dsDNA
  3. a copy of the viral genome is integrated into the host genome. this is called a provirus
  4. transcription of the new viral RNA
  5. translation into proteins
  6. packaged into new mature virions
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3
Q

what is a key way cancer passes through animals (not humans)?

A

retroviruses

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4
Q

what caps the end of retroviral RNA?

A

Long terminal repeats (LTR) which are strong drivers of transcription

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5
Q

what is RSV?

A
  1. Respiratory syncytial virus
  2. an acute retrovirus
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6
Q

what do acute retroviruses have?

A

an extra gene called src that can cause fast tumourigenesis

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7
Q

what are present in the host cell chromosome?

A

version of src called c-src
this is an proto-oncogene

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8
Q

what do slow retroviruses do?

A
  1. integrate the dsDNA provirus next to the c-src gene
  2. both the provirus and the oncogene are transcribed together
  3. making a new virus but also activating the oncogene
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9
Q

what do proto-oncogenes control?

A

growth and proliferation
control of cell cycle
apoptosis

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10
Q

are oncogenes associated with certain cancers?

A

yes different driving mutations in different tissue types cause different cancers

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11
Q

how can we detect oncogenes?

A

An in vitro transformation assay
1. use normal cells as a monolayer
2. infect a normal cell with the virus
3. transformation of cell
4. overcome the contact inhibition and grow
5. piling of cells = a tumour
6. can see cells on an EM as there is a big change in morphology to be more mesenchymal

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12
Q

what are the properties of transformed cells?

A
  1. Altered morphology
  2. loss of contact inhibition
  3. Anchorage independent - ability to grow without attachment
  4. immortalisation
  5. reduced requirement for mitogenic growth factors
  6. high saturation density
  7. inability to halt proliferation in response to deprivation of growth factors
  8. increased transport of glucose to meet higher metabolic requirements
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13
Q

how can oncogenic activity be detected?

A
  1. DNA extracted from carcinoma to chemically transformed fibroblasts
  2. introduced to normal cells
  3. formation of morphologically transformed cells
  4. check they are tumourigenic by putting into a mouse
  5. we can use this method to identify stretches of DNA with tumourigenic activity
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14
Q

How do slow acting retroviruses cause cancer without extra genes?

A

the provirus integrates next to the cellular oncogenes

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15
Q

ALV as an example of a slow retrovirus

A
  1. ALV integrates directly upstream exon 2 of the c-myc gene
  2. it faces the direction of transcription
  3. uses the long terminal repeats to drive transcription of the proto-oncogene making it an oncogene
  4. due to survival advantage it is more likely to integrate at one of these sites
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16
Q

How common are cancer-causing retroviruses in humans?

A

not very many known but they are very common for animals

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17
Q

what is the only known human cancer causing retrovirus?

A

Human T cell leukaemia virus

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18
Q

what would be easier if most human cancers were caused by retroviruses?

A

treatment and vaccination

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19
Q

what have we learn from animal retroviral cancers and experiments?

A

that human cells have cellular oncogenes that are hijacked during the process of transformation
(functions tend to be for growth and proliferation)

20
Q

what is epidermal growth factor receptor?

A
  1. a retroviral oncogene
  2. a tyrosine kinase receptor
  3. the most frequent amplification event in over 90 tumours
  4. Glioblastoma, breast, lung
21
Q

how is EGFR signalling deregulated in cancer?

A
  1. mutations that effect the structure of EGFR can cause ligand independent firing and the signal can get stuck on
  2. mutations that cause over expression which also leads to ligand independent firing
22
Q

how does normal EGFR signalling work?

A
  1. a growth factor binds to make the tyrosine kinase a duplex
  2. once the domain has dimerised then it will send the signal to trigger phosphorylation
23
Q

what is K-Ras?

A

an oncogene where mutation is common in a lot of cancers.
Change of function mutation.

24
Q

what makes K-Ras unique?

A

Its mutation is very localised.
In a sample of 10,000 tumours 98% had the mutation in codon 12

25
Q

what other genes are in the K-Ras family of oncogenes?

A
  1. H-Ras
  2. N-Ras
26
Q

what does K-Ras present?

A

A major challenge as it is present in a large variety of tumours and it is a focus of developing treatment

27
Q

what is the process of Ras activation and downstream signalling?

A
  1. Inactive Ras is bound to GDP
  2. GEF induces the exchange of GDP to GTP
  3. Active Ras is bound to GTP
  4. downstream phosphorylation events include the MAP-kinase pathway and other cancer driving signalling
  5. GAP causes GTP hydrolysis to GDP and inactivate Ras
  6. signalling process stops
28
Q

what is GEF?

A

guanine nucleotide exchange factor

29
Q

what is GAP?

A

Ras-GTPase activiting protein

30
Q

how is Ras signalling altered in cancer?

A
  1. A mutation in NF1 prevents Ras from returning to the inactive state and keeps signalling active
  2. signal epigenetic changes
  3. drive proliferation
31
Q

what is NF1?

A
  1. neurofibromatosis 1
  2. a common tumour suppressor gene lost in CRC, AML, neuroblastoma
  3. GTPase activity of Ras lost
32
Q

how does chromosomal translocation lead to C-myc over-expression in Burkitt’s lymphoma?

A
  1. A reciprocal translocation of the IgH heavy chain next to C-myc
  2. uses enhancers to drive transcription
  3. activating mutation
33
Q

what is Myc?

A

A major oncogene activated by translocation, amplification, and deregulation

34
Q

what genes are in the myc family and myc interactors?

A

C-myc: oncogene
N-myc: oncogene
L-myc: not really an oncogene
HLH transcription factor (helix-loop-helix)
TAD domain: topologically associating domain, interacts with proteins to control transcription
Co-activators or co-repressors: Max and Mad

35
Q

what is the function of the myc protein?

A
  1. Lots of signalling events feed through myc and it regulated a huge number of genes
  2. Works with lots of other proteins
  3. intracellular and extracellular signals
36
Q

what can mutations in myc lead to?

A

constant activation and results is many phenotypes including increased proliferation

37
Q

what can trigger myc signalling?

A
  1. growth factors
  2. cytokines
  3. cell adhesion
  4. contact-inhibition
  5. TGFß
  6. differentiation
38
Q

what can myc signalling cause that drives cancer?

A
  1. growth and proliferation
  2. prevent differentiation
  3. Immortalisation
  4. transformation
  5. Angiogenesis
  6. migration
  7. Apoptosis or senescence
  8. genomic instability
39
Q

what can myc acts as?

A

an activator or repressor depending on what is bound to.
It can also interact with epigenetic factors
Myc and max = activator
Myc, max and Miz = inhibitor

40
Q

Do different oncogenes interact?

A

Yes and it is critical for tumorigenesis.
mostly 1 mutation isn’t enough to cause cancer but complementary oncogenic mutations can cause tumours

41
Q

what 2 mutations often occur together?

A

Ras and myc.
Ras signalling can lead to a mutation that can stabilise the myc mutation

42
Q

Why can finding treatment for cancer be difficult?

A

due to the massive variation in cancer phenotypes

43
Q

what is p53?

A

A tumour suppressor gene

44
Q

what mutations can complement oncogene mutations?

A

Mutations in tumour suppressor genes

45
Q

why are oncogenes hard to design targeted treatments for?

A
  1. they mostly encode transcription factors
  2. So they do not have active sites so can’t easily inhibit them
46
Q

how can you use cancer mutations against it?

A
  1. Mutations accumulate and cells become dependent on 1 proliferation pathway
  2. This means once cancer reaches this stage then we can design targeted treatment without having to target the oncogene itself
47
Q

how do oncogenes keep the cells alive?

A
  1. hijack replication pathways and prevent safe guarding mechanisms for doing their function
  2. if we can knock out these pathways them we can force apoptosis or senescence

Cellular and Molecular pathology (25 decks)

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