Oncogenes and tumour suppressors

Question 1

Define proto-oncogene

Answer 1

A gene that codes for essential proteins involved in maintenance of cell growth, division and differentiation

Question 2

Define oncogene

Answer 2

A gene that is a mutated form of a gene involved in normal cell growth (proto-oncogene)
Protein product does not respond to control influences

Question 3

How can a proto-oncogene be activated to an oncogene?

Answer 3

1. Mutation in coding sequence - point mutation/deletion –> aberrantly active protein
2. Gene amplification - multiple gene copies –> overproduction of normal protein
3. Chromosomal translocation - chimeric genes
4. Insertional mutagenesis - e.g. viral infection

For 3 and 4 –> strong enhancer increases normal protein levels (e.g. Burkitt’s lymphoma) OR fusion to actively transcribed gene overproduces protein or fusion protein is hyperactive (Philadelphia chromosome)

Question 4

How do oncogenes disrupt cellular pathways?

Answer 4

Proto-oncogenes code for proteins that have important functions in normal cells
Diff proto-oncogene proteins are active at numerous sites in cell, including activity as receptor ligands and receptors (on plasma membrane, in cytoplasm and in nucleus) as signal transduction proteins, as TFs, etc. - involved in transcription, translation and cell proliferation

Mutation to the oncogene results in a protein that is aberrantly expressed, over-expressed or aberrantly active

A change in a single protein is enough to keep cell in proliferative state

Question 5

How have rare heritable cancers led to an understanding about tumour suppressor genes?

Answer 5

1st TSG discovered by studying retinoblastoma, a rare malignant cancer of neural precursor cells in immature retina

• Arises from cells converted to cancerous state by unusually small no. of mutations
• 2 forms: hereditary and sporadic
• Sporadic disease usually involves 1 eye and 1 tumour
• Hereditary disease - multiple tumours usually arise independently, affecting BOTH eyes
• Hereditary disease caused by mutation of RB1 TSG on chromosome 13q14 - deletions of same locus found in tumour cells from some patients w/sporadic disease –> suggested that cancer may be caused by loss of critical gene in chromosomal region
• Using known location of chromosomal deletion, gene whose loss appeared to be critical for cancer development (Rb gene) was cloned and sequenced
• Those who suffer w/hereditary from have a deletion/loss-of-function mutation in 1 copy of Rb gene in every cell of body –> cells predisposed to becoming cancerous, but only do if somatic mutation damages 1 good copy of Rb gene
• In patients w/sporadic disease, non-cancerous cells show no defect in either copy of Rb gene, while cancerous cells are defective in both copies

Question 6

What are the roles of p53?

Answer 6

Cell cycle regulator - guardian of the genome

• P53 upregulates transcription when triggered to produce proteins that try to resolve damage:
• metabolic homeostasis
• antioxidant defence
• DNA repair
• growth arrest
• senescence

If damage too severe –> apoptosis

Question 7

How are successive gene mutations thought to lead to clinical cancer?

Answer 7

Proto-oncogene + defective TSG OR oncogene + normal TSG –> cell growth and proliferation –> cancer

Oncogenes are dominant, TSGs are recessive
TSGs - 2 hit hypothesis - both copies must be damaged to cause cancer

Question 8

Explain, with an example, how mutation of a proto-oncogene can disrupt normal cell division

Answer 8

• Mutant RAS has aberrant activity
• Normally, RAS exists as protein on its own
• Upon binding GTP, RAS becomes active and interacts with protein called RAF
• Signals via phosphorylation type events
• RAS then passes signal onto other proteins within signal transduction cascade
• As a result, cell enters proliferative phase
• Turned off – GTP hydrolysed to GDP + P by RAS
• Mutant RAS fails to dephosphorylate GTP –> GTP persists –> RAS remains active
• Inappropriate increased signalling of RAF
• Increased proliferation stimulus
  RAS pathway is part of MAPK