Oncogenes

Question 1

What is an oncogene?

Answer 1

A gene which has the potential to cause cancer when under specific conditions.

Question 2

What is a tumour virus?

Answer 2

A DNA or RNA virus that is acutely or slowly transforming and can cause cancer within cells.

Question 3

Why doesn’t the integration of a retrovirus into a host’s genome kill the cell?

Answer 3

The provirus needs to be transmitted onto daughter cells during mitosis to form viral particles.

Question 4

What is a slowly transforming virus?

Answer 4

A virus which causes cancer after many months of viraemia through the insertional activation of an oncogene.

Question 5

What is a acutely transforming virus?

Answer 5

A virus which causes a tumour rapidly due to a viral oncogene.

Question 6

What is the genetic difference between slow and acutely transforming viruses?

Answer 6

Acutely have a viral oncogene.

Question 7

What is a viral oncogene?

Answer 7

They are homologous to cellular DNA in hosts, with similar nucleotide sequences suggesting that one was derived from the other.

Question 8

What did the discovery of viral oncogenes result in?

Answer 8

The discovery of human oncogenes, as the homologous sequences must also have the potential to cause cancer.

Question 9

What is the link between the Simian Sarcoma Virus and oncogenes?

Answer 9

The V-sis oncogene that causes a sarcoma from the infection of SSV, is homologous to the beta chain of PDGF. PDGF normally functions via paracrine signalling but was found to also have autocrine signalling. Self stimulation increases the risk of cancer.

Question 10

What evidence is there that PDGF is linked to sarcomas?

Answer 10

Osteosarcomas and gliomas where found to secrete PDGF and have PDGF recpetors for self stimulation.

Question 11

What is a GF and which are at risk of causing cancer?

Answer 11

GF control cytoplasmic signalling to drive proliferation.

EGF, IGF, TGFalpha and beta, Haematopoietic GF

Question 12

What is the belief now about the association of retroviruses and cancer?

Answer 12

Retroviruses are not involved in cancer, except HTLV1, but led to the discovery of similar oncogenes in humans.

Question 13

How was the role of in c-Myc Bursal lymphomas found?

Answer 13

Avian leukosis virus causes lymphomas in chickens. It is a slowly transforming retrovirus that integrates close to c-myc gene. This shows that there is a homologous sequence to the virus near c-myc. Insertion at c-myc leads to deregulated gene expression.

Question 14

What is the lag phase?

Answer 14

The time interval before a random provirus insertion occurs sufficiently close to c-myc by chance.

Question 15

What happens when c-myc expression is deregulated?

Answer 15

The normally low level, regulated protein causes high levels of transcription of its protein, leading to constitutive activation of c-myc.

Question 16

What causes Burkitt’s lymphoma?

Answer 16

A chromosomal translocation between the c-myc gene on chromosome 8 with an Ig gene on chromosome 2, 14 or 22. Causes constitutive synthesis of c-myc due to the Ig gene enhancer. = B cell tumour

Question 17

What is the normal function of myc?

Answer 17

It is a TF, produced at a transient pulse for proliferation after GF stimulation. It heterodimerises with Max to activate transcription of growth genes.

Question 18

What is the function of Max homodimerisation?

Answer 18

Predominates in non-stimulated cells to repress transcription.

Question 19

What is the problem with gene amplification?

Answer 19

An increase in the number of copies of a gene leads to over expression and can be used as a prognostic indicator and can cause early relapse.

Question 20

How are RTK and TK domains implicated in the development of cancer?

Answer 20

An AA change of partial deletion in its genes can cause constitutive TK activity, independently to GF = anti-apoptotic and proliferation signals
Gene amplification and overexpression can lead to homodimeristaion and constitutive activation

Question 21

Give two examples of cancer caused by overexpression of genes.

Answer 21

HER2 in breast cancer

EGFR in lung cancer

Question 22

What is pp60cSrc?

Answer 22

A non-receptor TK that does not require an extracellular signal. It has an intracellular SH2 domain that binds target proteins. Src induces intracellular signalling.

Question 23

How Src associated with cancer?

Answer 23

Found to have increased activity in >50% of cancers due to overexpression e.g. colon, liver, lung, breast pancreatic.
A mutation can lead to the loss of tyrosine-527 which acts as a block for the signal transducing conformation. Loss of this locks TK in its signalling form.

Question 24

What is a chimeric protein?

Answer 24

A protein with aberrant functions as a result of chromosome translocations within the coding region of a gene. This causes transcription to start as one protein but finish as another. It deregulates TK for uncontrolled proliferation.

Question 25

What is the translocation involved in promyelocytic leukaemia?

Answer 25

PML-RARalpha

Question 26

Which is the most frequently mutated oncogene in cancer?

Answer 26

Ras (H,K,N)

Question 27

What does the ras oncogene code for?

Answer 27

p21ras - G protein regulated by GTP binding.

Question 28

How does ras become constitutively active?

Answer 28

Mutations within 12, 13, 61. Can lead to loss of intrinsic GTPase activity e.g. in carcinogen induced cancers in smokers

Question 29

How can mutations in oncogenes be tested?

Answer 29

Cell transfection assay identifies transformed loci.

Question 30

Why is lag present in tumour development?

Answer 30

Multiple oncogenes and mutations are involved in the development. Lag occurs whilst the other genetic mutations arise, altering the genotype.

Question 31

How might an oncogene be altered?

Answer 31

Altering the function through:
-Point mutations at specific sites
-Chimeric fusion through translocation
Altering expression:
-Chromosomal translocations that change the regulatory sequences influencing it