2: Oncogenes & Tumour Suppressor genes Flashcards
Define proto-oncogene
Genes that code for proteins involved in maintenance of cell growth, division and differentiation
Define oncogene
A result of a single mutation of a proto-oncogene.
Its protein product no longer responds to control influences
State 4 ways in which mutation of oncogene occurs
- Point mutation of deletion
- Gene amplification (multiple gene copies, overproduction)
- Chromosomal translocation (overproduction of protien due to chimaeric genes)
- Insertional Mutagenesis (fusion of viral gene, overproduction of protein or produces hyperactive protein)
Give examples of oncogenic mutations
Burkitt's Lymphoma (chromosomal translocation) Philadelphia Chromosome (Insertional mutagenesis)
What is Philadelphia chromosome?
ABL gene translocation - chromosome 9 to 22
Give 3 pathways by which cell proliferation can be activated
- Nuclear/cytosolic receptor: binding of growth factor (GF) translocates it to DNA -> upregulation of transcription/translation -> proliferation
- Tyrosine-Kinase receptor: binding of GF to receptor causes phosphorylation cascade -> proliferation
- G-protein Coupled Receptor: binding of GF -> kinase cascade -> phosphorylation -> proliferation
Where in the cell do proto-oncogenes regulate cell division?
- Receptors on plasma membrane that bind GF (e.g. MET codes for tyrosine kinase receptors)
- Proteins involved in signalling pathways that promote cell proliferation (e.g. RAS/RAF)
- In the nucleus - proliferative transcription factors (e.g. MYC/fos/jun activate expression of many pro-proliferative genes)
How does mutant RAS cause cancer?
- Normally RAS binds to GTP and is activated
- Active RAS then activates RAF, which activates signalling cascade leading to proliferation
- RAS is deactivated by dephosphorylation of GTP to GDP
- Mutant RAS can’t dephosphorylate and remains active
Examples of oncogenes
SRC MYC JUN H-RAS K-RAS
Define Tumour Suppressor Gene
Code for proteins that regulate cellular proliferation and maintain cellular integrity
How many copies of TSGs and proto-oncogenes in each cell in our body?
2
What happens if you damage one copy of TSG?
The remaining TSG is able to compensate for the loss, tumour suppressor function is NOT lost. Does not promote cancer.
What happens if you damage one copy of proto-oncogene?
Becomes an oncogene - this is a DOMINANT effect.
Promotes cancer
What are the features of inherited cancers?
- Family history of related cancers
- EARLY age of onset unlike other cancers
- BI-LATERAL tumours in paired organs
- SUCCESSIVE tumours
- Tumours in MULTIPLE organs of same person
Define retinoblastoma
Malignant cancer of developing retinal cells.
How does retinoblastoma present
It is a sporadic disease involving ONE eye (i.e.
Hereditary cases can be unilateral, bi-lateral or multifocal as additional tumours can develop.
Cause of retinoblastoma
Mutation in RB1 tumour suppressor gene
Chromosome 13q14
What is the role of RB1 tumour suppressor gene in cell cycle
Encodes nuclear protein involved in cell cycle - prevents excessive cell growth by inhibiting cell cycle progression
What is the overall function of tumour suppressor genes
To suppress the neoplastic phenotype (i.e. inappropriate cell growth)
How is p53 different to other TSGs?
Requires mutation on only ONE copy to become oncogenic, unlike other TSGs which require damage to both copies
What is p53 normally bound to when inactive?
MDM2 protein
Give examples of stimuli that can activate p53
- DNA damage
- Oncogene activation
- Hypoxia
- Oxidative stress
How does p53 have its effects?
- Acts like a transcription factor - binds to p53 target genes
- Protein-protein interactions (apoptosis)
What are the effects of p53 in mild and severe stress?
In mild stress: - Metabolic homeostasis - Antioxidant defence - DNA repair - Growth arrest In severe stress: senescence and APOPTOSIS
What disease is APC gene associated with?
Familial adenomatous polyposis coli (benign)
- Deletion in 5q21 resulting in loss of APC tumour suppressor gene
- Multiple benign adenomatous polyps of COLON
- 90% risk of developing colorectal carcinoma
What is the role of APC gene
Cell adhesion and signalling
How does APC function
Involved in WNT signalling pathway
Controls activity of beta-catenin thereby preventing uncontrolled growth
How do successive gene mutations lead to colorectal cancer?
- APC mutation -> Hyperproliferative epithelium (benign)
- K-ras mutation -> ADENOMA (still benign)
- p53 mutation -> CARCINOMA (malignant) -> METASTASIS (death)
How are oncogenes different to TSGs?
Oncogenes:
- Usually activated by translocation/point mutations (TSG: deletion/mutations)
- Rarely hereditary unlike TSGs
- DOMINANT
- Broad tissue specificity
- Usually leads to Leukaemia/lymphoma (TSG: solid tumours)
Hallmarks of cancer
Disregard of signals to stop proliferating Disregard of signals to differentiate Capacity for sustained proliferation Evasion of apoptosis Ability to invade Ability to promote angiogenesis
List 5 TSGs
p53 APC p16-INK4A BRCA1 PTEN MLH1
Functional classes of TSGs?
- Regulates cell growth/proliferation
- Regulates cell cycle
- Maintains cellular integrity
- Nuclear transcription factors (p53)
- DNA repair proteins
- Cell adhesion molecules
- Apoptosis regulators
