Oncogenes

Question 1

What are oncogenes?

Answer 1

Alleles which if mutated act in a “dominant” or positive (gain-of-function) fashion
Mutations usually affect one allele only
Not special cancer genes but normal genes important in growth control
Normal- protooncogenes, oncogene- activated

Question 2

How were oncogenes first discovered?

Answer 2

elements in certain tumour-producing retroviruses that were responsible for their carcinogenic properties
viral oncogenes were close homologues of normal cellular genes – and that these cellular genes could become carcinogenic if ‘activated’ by various means

Question 3

How do retroviruses use oncogenes?

Answer 3

Normal cellular genes recombined into the retroviral genome and inappropriately expressed under the powerful viral promoters- Long Terminal Repeats
Produce tumours quickly after infection
Transcribed cellular oncogene RNA (no introns) becomes recombined into the retroviral RNA genome

Question 4

What is insertional mutagenesis?

Answer 4

Some retroviruses are oncogenic but do not carry oncogenes, the provirus integrates beside a cellular proto-oncogene which is then under the control of the viral promoters (or enhancers) and is inappropriately expressed.
leukaemia of chickens where c-myc is overexpressed

Question 5

How are oncogenes activated?

Answer 5

Retrovirus Promoter Insertion (insertional mutagenesis)
Point mutation
Amplification and Truncation
Inappropriate regulation of expression

Question 6

What is Ras?

Answer 6

A G protein which binds GTP and is a key player in signal transduction
Family has three members; K-ras, H-ras, N-ras

Question 7

How can point mutation in Ras lead to cancer?

Answer 7

point mutation, usually at either codon 12 or 13, such that  the mutant protein cannot hydrolyse GTP, the Ras protein remains locked in the Ras-GTP active configuration and so the signalling pathway remains permanently activated
Normal ras (glycine at codon 12) -> mutated ras (valine at codon 12) - missense mutation (K-ras)

Question 8

Describe oncogene amplification

Answer 8

Epidermal Growth Factor Receptor (EGF-R) overactive when gene amplified to many 100s of copies- more sensitive to EGF stimulation (squamous cell carcinomas)

Question 9

Describe oncogene truncation

Answer 9

Epidermal Growth Factor Receptor (EGF-R) overactive when extracellular domain of EFG-R truncated, constitutively activates it so cell constantly receives EFG like signals

Question 10

Examples of other oncogene amplifications

Answer 10

C-erb-B2 (HER2) is amplified in many breast cancers (treated by blockade of its ligand Herceptin)
N-myc oncogene- neuroblastoma (childhood)

Question 11

Describe inappropriate regulation of expression

Answer 11

Myc activated by inappropriate regulation of its expression, deletion of regulatory sequences for the promoter/ use of inappropriate promoter

Question 12

Example of inappropriate regulation of expression

Answer 12

Burkitt’s lymphoma- C myc and IgG 8/14 translocation

B lymphocyte- IgG normally high expressed, C myc now highly expressed

Question 13

Examples of growth signalling pathways oncoproteins are involved in

Answer 13

• Growth factors: sis (Simian sarcoma virus) platelet derived growth factor
• Receptor: erbB (Avian erythroblastosis virus) epidermal growth factor receptor
• Signalling protein: abl (Abelson mouse leukaemia virus) tyrosine kinase or ras (Rat sarcoma virus) GTP-nucleotide binding molecular switch
• Transcription factor: myc (Myelocytomatosis virus) binds DNA stimulates proliferation and regulates apoptosis