Oncogenes Flashcards
What is a Driver Mutation?
A mutation which directly or indirectly offers a cell a selective growth advantage
What is a passenger mutation?
A mutation which does not directly or indirectly offer a cell a selective growth advantage
Number of driver and passenger mutations per cell?
Driver: 5-8
Passenger: 100s
Examples of positive regulators for cancer susceptibility genes
Classical Oncogenes
Telomerases
Anti-apoptotic genes
Examples of negative regulators for cancer susceptibility genes
Classical tumour suppressor genes
Indirectly acting tumour supressor genes
Apoptotic genes
Number of casual contributing cancer genes?
729
Role of proto-onocgenes in growth signalling pathways
Promote cell proliferation
Inhibit apoptosis
What do oncogenes do
Increase the activity of a specific protein due to mutation
Are oncogenes genetically dominant or recessive
Dominant, only 1 allele usually needs to undergo the mutation to contribute to cancer development
How do oncogenes drive cell proliferation?
Resist apoptosis
Replicative immortality
Self-sufficient growth signalling
Evade growth suppressors
6 Classes of cellular oncogenes
Transcription factors
Growth factors/mitogens
Growth factor/mitogen receptors
Cell death inhibitors
Cell cycle regulators/drivers
Signal transduction component
How do proto-oncogenes become oncogenes via genetic changes
Amplification of gene - Overexpression of normal, growth-stimulating protein
Translocation/transposition of gene - Overexpression of normal, growth-stimulating protein
Point mutation - Hyperactive or degradation-resistant protein
Mitogen and mitogen receptors
Mitogens stimulate cell division by binding to receptor in cell membrane
EGFRs (Epidermal growth factor receptors) mutated in 40-50% brain tumours, 20% breast cancers, 15-30% ovarian cancers
EGFR mutations can involve amplification or deletion of gene, leading to their being too many or too little receptors for mitogens
Signal Transduction components
Signalling protein - Activated by growth factor binding to receptor
Ras inactive when bound to ADP
Raf kinase is responsible for production of ATP from mitogen bound ADP in activating signalling
Ras activation usually transient
Ras intrinsic GTPase hydrolyses GTP to GDP
Part 2 signal transduction
30% cancers have Ras mutation
Mutation on codons 12, 13 or 61 can lead to inactive GTPase activity, leading to constant cell signalling and proliferation
Leads to tumour formation
Transcription factors with oncogenes
Myc is a protein responsible for cell growth and division
Oncogenes overexpress Myc
Amplification - leads to 100s of copies of oncogene, cancer causing
Point mutation - Stabilizes Myc
Translocation increases gene expression leading to cancer e.g. Burkett’s lymphoma increases mutant B-cell proliferation
Cyclin D and Cdk4
Cyclin D overexpression is initiated by CCND1
Found in 35% oesophageal cancers, 15% of breast and bladder cancer
50% in breast cancers
Mutation leads to unauthorized entry to S-phase from G1
CDK4 gene forms Cdk4 in G1 which is amplified in 12% gliomas, 11% sarcomas
Restriction point mechanism
- In G0 and G1, E2F is bound to and inhibited by Rb protein
- To enter cell cycle, cyclin D associates with Cdk4 or Cdk6
- Cdk then phosphorylates Rb protein releasing it from E2F
- E2F is free to transcribe genes for G1/S transition
What does overexpression of CCND1 or CDK4 lead to?
Unregulated phosphorylation of Rb protein
What is apoptosis and what does it cause?
Programmed cell death which results in controlled cell suicide
-Cells shrink and condense
-Cytoskeleton collapses
-Nuclear envelope disassembles
-Nuclear chromatin condenses and breaks into fragments
- ‘Eat me’ signal - Cell engulfed by macropage
Intrinsic vs extrinsic pathway
Intrinsic - Depends on release into cytosol of mitochondrial proteins usually found in intermembrane space
Extrinsic - Triggered by extracellular signal proteins binding to cell surface death receptors
What is the intrinsic pathwayof apoptosis inhibited by?
Bcl2 proteins
Proto-oncogenes - Anti-apoptotic
Tumour-suppressor genes - Pro-apoptotic
Bax-Bax homodimer -> Apoptosis -> cells die
Bax-Bcl2 heterodimer -> Normal cell
Bcl2 overexpression -> Apoptosis blocked -> Cell immortalized
How does MDM2 regulate TSG activity
- MDM2 ubiquitinates lysines in p53 C-terminal domain
- Any remaining p53 exported from nucleus
- MDM2 and p53 phosphorylated
- p53 accumulates
- MDM2 found to amplify in 19/28 tumour types
- MDM2 mutations prevent p53 accumulation
What is hayflick limit
Normal cells cease to divide after 50-70 doublings
What happens to telomerases after division
Get shorter
What occurs with senescent behaviours
- telomerases change shape
- Shortening becomes critical and cells withdraw from cycle
- Cancer cell immortalisation caused by increased gene expression of telomerases by oncogenic mutations
What cancer types are there increased telomerase expression?
All major cancer types
