Tumour Suppressors Flashcards
What is a tumour suppressor? (1)
A gene that protects a cell from one or more steps on the path to cancer
What is a tumour suppressor? (2)
A gene which, when mutated, predisposes an individual to cancer
What are the 3 classes of TSGs?
Gatekeepers
Caretakers
Landscapers
What do gatekeeper TSGs do?
Prevent growth of potential cancer cells
What do caretaker TSGs do?
Maintain the integrity of the genome
What do landscaper TSGs do?
Control the cellular microenvironment
What are the 10 hallmarks of cancer?
Resisting cell death Avoiding immune destruction Enabling replicative immortality Evading growth suppressors Sustaining proliferative signalling Genome instability and mutation Inducing angiogenesis Activating invasion and metastasis Tumour-promoting inflammation Deregulating cellular energetics
What 2 kinds of retinoblastoma are there?
Familial (40%) and sporadic (20%)
When do familial retinoblastomas appear compared to sporadic?
At a younger age
Where can familial retinoblastomas develop?
Often in both eyes, can also be accompanied by tumours in other organs
What was Knudson’s two-hit hypothesis?
Cancer is a multi-hit disease i.e. it is the result of accumulated mutations.
Why does a familial mutant Rb allele mean the carrier will develop bilateral disease much earlier than in sporadic case?
The first somatic mutation in a familial Rb mutation case leads to two mutant Rb gene copies. The chances of this happening on both sides is much higher. In sporadic cases, 2 somatic mutations must occur to reach the same stage.
Name the 7 ways of eliminating normal Rb function
- Non-disjunction (Chromosome)
- Non-disjunction and replication
- Mitotic recombination
- Gene conversion
- Deletion
- Point mutation
- Promoter methylation
Name 2 key tumour suppressor genes
p53
PTEN
How was p53 originally identified?
By its interaction with viral proteins
SV40, Adenovirus and Papillomavirus
What do p53 mutations do?
Some don’t stop cancer developing, some actively help cancer develop.
What proportion of human cancers is p53 mutated in?
~50%
What happens in the majority of cancers that don’t have p53 mutations?
There are other mutations that affect the p53 activation pathway or other indirect ways to inactivate p53.
In which rare, autosommal dominant condition do patients have a germline TP53 mutation?
Li-Fraumeni Syndrome - develops early and aggressively
What is the protein structure of p53?
Nuclear phosphoprotein. Acts in tetrameric form.
What is the function of p53?
Transcription factor that recognises a 10bp consensus sequence in promoters
Where are p53 mutations clustered?
Exons 5-8
Where are the p53 mutation hotspot?
Amino acids 175, 248, and 273 - DNA binding domains.
What do mutant p53 do to normal p53?
Interfere with normal p53 function.
Why does mutant p53 interfere with normal p53 function?
Because p53 exists as a tetramer, if even one of the units is mutated the protein will not function.
How is p53 expressed in the absence of damage?
At very low levels. T1/2 = 20 minutes
What functions does p53 have?
It depends on what the specific cell needs at any one time, both in response to stress and in normal conditions.
Can these functions be antagonistic and spontaneous?
Yes
What does p53 need to exert its effect?
Some require gene transcription (transactivation), some don’t.
Where are the functions of p53 performed?
Some in the nucleus, some in the cytosol.
What can p53 do as the guardian of the genome?
- Cell cycle arrest
- DNA repair
- Block angiogenesis
- Apoptosis
What can cell cycle arrest lead to?
- Senescence
- Return to proliferation
How is p53 activated?
By post-translational modifications
How do the post translational modifications give p53 their specific function?
Via a mixture of modifications at different combinations of sites along p53
What is MDM2?
The chief cellular antagonist of the p53 tumour suppressor gene
How is MDM2 induced?
By p53 to moderate itself
What does MDM2 do?
Degrades p53
What happens to MDM2 if a mutation is detected?
It is stopped so p53 function can be upregulated
What is the Warburg effect?
p53s effect on metabolism - cancer cells mostly use aerobic glycolysis to obtain energy instead of oxidative phosphorylation. This leads to lactic acid build up in the cytosol.
What are the 2 pathways to senescence?
- Replicative senescence
- Stress induced premature senescence
What is replicative senescence?
Occurs physiologically with age. Telomere shortening with each division as duplication is incomplete.
What is PTEN?
A tumour suppressor with phosphatase activity
What does PTEN do?
Dephosphorylates PIP3 to block cell proliferation.
What can induce PTEN?
p53
What is the oathway that normally activates PIP3?
PI(membrane bound, intracellular molecule) -(PI Kinases)-> PIP2 -(Phospholipase C) -> IP3 or
PI(membrane bound, intracellular molecule) -(PI Kinases)-> PIP2 -(PI3 kinase) -> PIP3
What is PIP3 normally used for?
To signal division and growth
What does PTEN convert PIP3 to?
PIP2
What percentage of prostate carcinomas have a PTEN mutation?
40-50%
What percentage of glioblastomas have a PTEN mutation?
25-50%
What percentage of endometrial carcinoma have a PTEN mutation?
35%
p53 + PTEN =
Apoptosis
p53 - PTEN =
Senescence
