Evading Growth Suppressors W6 Flashcards
How do normal cells control their
proliferation?
- Cell cycle checkpoints
- Tumor suppressor genes
- Protons-oncogenes
- External signals
- Contact inhibition
- Apoptosis and senescence
- Telomere length
Tumour suppressor genes
There are over 200 known tumour suppressor genes (TSG)
The three main TSGs are:
1. Cyclin / cyclin dependent kinases and cyclin dependent kinase inhibitors
2. Retinoblastoma protein
3. p53
Tumour suppressor genes
Different cyclins are expressed in different phases of the cell cycle and combine with different cdks
Each of these activated cdk complexes phosphorylates a different set of target proteins in the cell
- Retinoblastoma
Rb acts as a brake here keeping the cell in G1
Inhibits the genes necessary for progression into S phase
Phosphorylation of Rb releases the brake
Many cancers have a mutation in Rb causing….
constitutive activation of the cell cycle
Where was tumour suppressor gener discovered
In retinoblastoma
Cancer of the eye
Almost all die if left untreated
Thought to be proto-onco genes but the altered gene was named Rb and was found to be mutated in other cancers
The Rb gene is inactivated in cancer
Retinoblastoma - a tumour suppressor gene
• Some patients have a deletion of the Rb1 gene or point mutation
• Deletion or mutation encourage cell division
Inactivating mutations are called
recessive or
loss of function mutations
What is Rb?
Tumor suppressor gene
Stops the cell cycle at G1/S checkpoint if the conditions aren’t right for DNA replication - like a break
Is recessive at the cellular level so both alleles must be lost or mutated for cancer to develop
How can mutant Rb, which is a recessive gene cause cancer?
Retinoblastoma requires the loss of both functional copies of the Rb gene
Both allles get knocked out by mutation or deletion and so no functional Rb protein is left
Now the cell cant stop progressing through the cell cycle and cells divide uncontrollably
People inherit one mutated gene and later the other mutates
Sporadic cancers
Most common
occur due to random genetic mutations acquired during a person’s lifetime, rather than inherited from their parents.
Familial cancers
No identified mutation but runs in families
Hereditary cancers
Caused by a know inherited mutation that is present in every cell
- P53
Genomes bodyguard
Activated when there’s cellular stress
Mutations in this tumour suppressor gene causes dysregulated cell growth and proliferation and cancer
Interacts with CDK inhibitor p21
Acts as a break keeping the cell in G1 if there is damage until there is repair or apoptosis
What happens when there is DNA damage
Sensor proteins detect damage
They activate P53 via phosphorylation which stabilises P53
P53 activates P21 which inhibits CDK and the cell cycle stops at G1/S for repair or triggered apoptosis
Summary:
DNA damage → ATM/ATR → p53 → p21 → Cell cycle arrest → Repair or Apoptosis
What happens when there is no DNA damage
P53 stays inactive and is degraded by MDM2
Cells proceed through the cell cycle normally
No checkpoint activation as everything is functioning properly
What if P53 is mutated of lost
Happens in ~50% of human cancers.
Damaged cells don’t stop dividing → accumulate more mutations.
Cells with faulty DNA escape apoptosis → genomic instability.
This allows uncontrolled cell proliferation → cancer progression.
What is viral carcinogenesis
How viruses cause cancer
- Insert oncogenes
- Inactivated tumor suppressor genes
- Cause chronic inflammation
- Integrate into host genome
Key oncogenic viruses
HPV - not all as most infections are cleared from immune system
EBV - promotes polyclonal B-cell proliferation
HBV + HCV - activates proto-oncogenes and inactivated TP53 suppressor gene
2 catagories of cancer genes
Tumor suppressor
- normally block mitosis and must be knocked out for cancer to progress
Proto-onco
- normally pass on signals to grow and must be stuck in “on” mode for cancer to occur
What is the difference between tumour
suppressor genes and oncogenes?
- Tumor Suppressor Genes: The “Brakes” of the Cell Cycle
Inhibit cell division and prevent uncontrolled growth
- Oncogenes: The “Accelerators” of the Cell Cycle
Promote cell division and survival
