Oncogenes

Question 1

Start of tumour virology?

Answer 1

Peyton Rous 1911 found that a filterable agent from a chicken sarcoma could rapidly cause cancer when injected into another chicken.

Question 2

Types of tumour viruses

Answer 2

DNA viruses
RNA viruses - retroviruses
- acutely transforming
- slowly transforming

Question 3

Slowly transforming retroviruses mechanism

Answer 3

Cause tumours after many months of viraemia
Mechanism: insertional activation (=deregulation) of a cellular oncogene.
Insertion of gag - group specific Ag (virus core protein) pol - RNA dependent DNA polymerase and env - envelope proteins (binds target cell)
Long terminal repeat, contains transcriptional regulatory sequences - promotor and strong enhancer this helps the deregulated gene upregulate its expression

Question 4

Acutely transforming retroviruses mechanism

Answer 4

Cause tumours rapidly due to a viral oncogene (v-onc)
Insert gag, pol and env also v-onc
V-onc genes of acutely transforming retroviruses are homologous to genes in cellular DNA of the host species BUT they have mutational changes that deregulate the function of the encoded oncoprotein and they are expressed highly due to LTR enhancement.
Chicken evidence shows the viral onocogene is homologous to the genes in cellular DNA of the host species

Question 5

Normal cell signalling vs abnormal cell signalling

Answer 5

Normal: is the paracrine signalling pathways stimulation, extracellular growth factors
Abnormal: autocrine signalling, positive feedback loop
The cell can also be constitutively active due to mutations in Ras which mean sit doesn’t need to be stimulated or other down stream signalling molecule mutations and receptor mutation so they do not need extracellular signals.

Question 6

Where are retroviral genes derived from

Answer 6

They are derived from cellular genes involved in the signalling pathways driving cell proliferation and cell survival -RTK

Question 7

Examples of mutational changes to cellular oncogenes that can enable their contribution towards the initiation an progression of human cancer

Answer 7

Translocations - BRC-ABL
Also Burkett’s lymphoma which is a translocation between the c-myc gene in chromosome 8 and immunoglobulin gene loci on chromosomes 2,14,22 leading to a constitutive increase in synthesis of a normal c-myc protein
Can also be single base mutations adding, subtracting and replacing single bases or multiple (codons)

Question 8

What does Myc do?

Answer 8

Myc is a transcription factor
In normal cells, Myc accumulates shortly after growth factor stimulation
Accumulated Myc forms heterodimers with Max and this activates the transcription of growth related genes
In non-stimulated normal genes when Myc levels are low Max homodimers predominates and repress transcription of these genes
Deregulated expression of Myc causes constitutive expression of many growth related genes.

Question 9

Over expression can also be due to gene amplification - explain the types?

Answer 9

Normally one c-onc in the gene
Gene amplification more than one c-onc in the gene
Or
Double minute chromosomes these are fragments of extrachromosomal DNA- they have no centromere, circular, several kbp - Mbp
More gene copies –> higher level of expression

Over expression of Myc by gene amplification is another mechanism for Myc over expression in tumours

Question 10

What is an oncogene?

Answer 10

Positive stimulators growth gene

She mutated they are hyperactive and cause excess proliferation and angiogenesis leading to a tumour

Question 11

Burkitts lymphoma is a translocation of which chromosomes

Answer 11

Chromosome 8 with either chromosome 2, 14 or 22

C Myc translocation near Ig region and causes constitutively activated c Myc - B cell lymphoma

Question 12

What are Myc proteins

Answer 12

Transcription factors
Accumulate transiently in the cell after growth factor stimulation
Form heterodimers with Max and activate transcription of growth related genes
Most of the time there is little Myc so max homodimerises and represses gene transcription.
Deregulated expression of Myc leads to constitutive expression of many growth factors

Question 13

Changes in RTK in cancer

Answer 13

Amino acid change or partial deletions 
- result in constitutive tyrosine kinase activity 
- growth factor independent signalling 
Gene amplification and over expression 
- greater growth signals
- erbB-2/ HER2/neu in Breast cancer

Question 14

What is c-Src

Answer 14

It is non receptor tyrosine kinase 
Homologous to the viral oncogene v-Src 
Consists of 3 domains 
SH2 domain
SH3 domain 
Tyrosine kinase domain
Activates many intracellular signalling cascades 
Activity is increased in 50% of tumors

Question 15

Ras oncogene family

Answer 15

H-Ras
K-Ras
N-Ras

Question 16

What do the Ras family encode

Answer 16

P21ras which is a G protein

Question 17

What are the 2 main ways cellular oncogenes can be altered such that they contribute to human cancer

Answer 17

Affecting the function of the encoded oncoprotein
- this includes point mutations at specific sites (such as Ras) and chimeric fusion proteins such as BCR-ABL which results from chromosomal abnormalities
Affecting the expression of the an oncogene
- this can include chromosomal translocation which place the oncogene under the control of alternative, strong regulatory sequences such as enhancers