Lecture 3 - Genetics of malignancy 2 Flashcards
How do cancer cells affect the cell cycle?
They circumvent normal regulation
Tumour suppressor genes
- Genes whose absence leads to cancerous phenotype
- Supress or promote apoptosis. Can be thought of as brakes on cell proliferation
- Recessive usually at cellular genetic level but often show dominant inheritance in cancer predisposition syndromes
- Many tumour supressor genes e.g. RB and p53
Rb negatively regulates proliferation by acting as a brake until growth-factor receptor signalling received
Rb negatively regulates proliferation by acting as a brake until growth-factor receptor signalling received
Pro-growth pathway signal to overcome G1/S checkpoint
- Oncogenes short-circuit normal growth regulatory pathways
- Result of upregulation of TFs e.g. Myc involved in controlling expression of proliferation-associated genes.
This leads to increased cyclin D-Cdk4 activity (G1-Cdk).
(CCND1/CCND2 and CDK4 also act as proto-oncogenes, see slide 23 from last lecture).
Rb binds E2F, preventing S-phase entry
- Active Rb protein binds inactivated E2F protein
2.
When was Rb first identified?
Genetics as its loss causes childhood cancer Retinoblastoma
Knudson’s two-hit hypothesis for retinoblastoma
- One of the rarest forms of cancer
- Knudson was paediatrician who studied retinoblastoma
Two types:
Bilateral - Family history, even if successfully removed, life-long risk of developing other cancer types
Unilateral - No family history, patients can be cured by removing tumour and usually live healthy lives
Knudson used stats to understand how both forms were occurring
What are the most prevalent TP53 mutation sites
Ovaries (~47-48)
Colorectum (~44%)
Head and neck (~42%)
p53 - a tumour suppressor and “guardian of the genome”
p53 (gene TP53): a transcription factor that regulates genes involved in:
- Cell cycle arrest (p21 CIP1/WAF1)
- DNA repair (e.g. XPA)
- Inhibition of angiogenesis (e.g. TSP-1)
- Apoptosis (e.g. Killer/DR5)
p53 is stabilised following cell stress
E3 ubiquitin ligase binds Mdm2
Mdm add polyubiquitin chains (ubiquitylation of p53)
p53 degraded
X-rays cause DNA damage -> ATM/ATR kinase activation -> Chk1/Chk2 kinase activation -> Phosphorylation of p53
Phosphorylation of degraded p52 activates p53 and released Mdm2 and polyubiquitin chains which are degraded by proteosome
Stable, active p53 binds to regulatory region of p21 gene
Oncogenic signalling should lead to cell-cycle arrest or apoptosis
Oncogenic signalling to Myc -> excessive Myc production
-> Arf -> Inactive Mdm2
Arf -> Inactive Mdm2 causes degraded p53 to form stable, active p53
Stable active p53 -> cell cycle arrest or apoptosis
Why don’t elephants get cancer
Large and long lived, so would except high cancer rate
<5% of cancer
Elephants have multiple copies of p53 (humans have 2)
Up to 40 alleles of p53
Enabling replicative immortality - Telomerases
Ends of chromosomes protected by telomeres
Telomeres het progressively short with successive generations
Successive cell generations –> CRISIS
Reaches synasanse and can’t undego replication anymore
What do telomerases do>
Resynthesise telomeres
Telomerase is normally only expressed in germ cells and stem cells
Most cancer cells become immortal by expressing TERT (the telomerase gene)
Deregulation of cellular energetics - the Warburg effect
Normal cells divert most of their pyruvate to the Krebs/citric acid cycle. This is a very efficient way to produce ATP
However:
1. Requires oxygen
2. Leaves little for biosynthetic pathways
80% of cancers rely mostly on aerobic glycolysis for energy. Why?
Response to the hypoxic environment? Or source of biosynthetic building blocks?
