Lecture 3: Oncogenes

Question 1

What is a proto-oncogene?

Answer 1

The wild type allele (normal gene) of an oncogene. Mutation of this can create the oncogene.

USUALLY DOMINANT

Question 2

What is some early evidence of oncogenes and proto-oncogenes?

Answer 2

1911: Rous (RSV)
1914: Theodore Boveri

Question 3

When were oncogenes discovered?

Answer 3

1960: Nowell & Hungerford, evidence for casual role in genomic rearrangement

1969: Huebner & Todaro, proposed viral genes, integrated into genome, causing malignancy

1976: Stehelin et al, Showed RSV contained seq. not found in related, but non-transforming retrovirus

Question 4

How can retroviruses transform?

Answer 4

1. Integrated provirus activates adjacent cellular proto-oncogene (MMTV)
2. Provirus carries a ‘captured’ cellular oncogene (RSV)
3. Provirus-coded protein activates cellular genes (HTLV1)

Question 5

What are ‘viral oncogenes’?

Answer 5

1. DNA Tumour Viruses
2. SV40: Large T antigen binds and inactivates p53 and pRb - growing evidence for SV40 in brain cancers, NHL, lymphoma, and mesothelioma
3. Adenovirus:
   E1A - binds pRb and immortalises cells
   E1B(55K) - inactivates p53
4. HPV:
   E6 - interacts with p53 and activates telomerase
   E7 - interacts with pRb

Question 6

What sort of genes have oncogenic potential?

Answer 6

GF’s, GF-receptors, G-proteins, cytoplasmic tyrosine kinases, serine-threonine kinases, nuclear proteins, miRNAs

Question 7

How are proto-oncogenes activated?

Answer 7

1. Deletion or point mutation in coding seq.
2. Gene amplification
3. Chromosome rearrangement/ translocation

Question 8

What oncogene is activated by a point mutation?

Answer 8

RAS

1. Family of small GTP binding proteins
2. Involved in communicating between protein tyrosine kinases receptors and the Raf-MAP kinase pathway
3. This pathway activates TFs involved in cell cycle control
4. mutated in high % of human tumours
5. Correlates with poor prognosis
6. In cancers, the GTPase activity is lost, meaning RAS remain active for longer

Question 9

How can increased cell proliferation via RAS mutation be treated therapeutically?

Answer 9

MEK inhibitors such as selumetinib (AZD6244) can be used as a targeted therapy.

Question 10

What oncogene is activated by amplification?

Answer 10

Myc: seq specific DNA-binding protein

Myc has two roles: cell proliferation and cell death, depending on its interaction with other factors.

Interaction with MAX via bHLH-zip domains activates/represses target genes

In cancers, myc has deregulated expression

Neuroblastoma: N-myc amplification suppresses on the protein kinase C isoforms, altering transduction pathways

Question 11

What oncogene is activated by chromosomal translocation?

Answer 11

abl = tyrosine kinase

bcr-abl in chronic myeloid leukaemia (CML)

bcr = serine/threonine kinase activity essential for oncogene function

uncontrolled multiplication of myeloid stem cells

reciprocal translocation between chromosomes 9 and 22. 5kb portion of of 22 called ‘bcr’ join seq of abl exon 2 onwards from chr 9. Promoter and control regions of bcr (not abl) now regulate expression of chimeric protein.

Question 12

What are BRCA 1&2 genes

Answer 12

tumour suppressor genes - DNA repair

Question 13

Are oncogenes dominant or recessive?

Answer 13

Dominant