What is a tumour suppressor gene?
A gene that protects the cell from one or more steps on the path to cancer.
A gene which, when mutated, predisposes an individual to cancer
What are the different classifications for tumour suppressor genes?
What do gatekeeper tumour supressor genes do?
Prevent growth of potential cancer cells
What do caretaker tumour suppressor genes do?
Maintain the integrity of the genome
What does failure of the caretaker tumour suppressor genes lead to?
Genetic instability, which is one of the hallmarks of cancer
What do landscaper tumour suppressor genes do?
Control the cellular microenvironment
Why is the cellular microenvironment important in cancer?
Cells around can have a positive or negative effect on cancers .
Which of the hallmarks of cancer do tumour suppressor genes stop?
- Deregulating cellular energetics
- Sustaining proliferative signalling
- Evading growth suppressors
- Tumour-promoting inflammation
- Activating invasion and metastasis
- Inducing angiogenesis
- Genome instability and mutation
What hallmarks of cancer do tumour suppressor genes encourage?
- Avoiding immune destruction
- Enabling replicative immortality
- Resisting cell death
What are the two types of retinoblastomas?
- Sporadic (60%)
- Familial (40%)
How do sporadic and familial retinoblastomas differ?
- Familial retinoblastomas appear at a younger age
- Familial retinoblastomas often develop in both eyes, and can be accompanied by tumours in both organs
What can be deduced from the differences between sporadic and familial retinoblastomas?
Something predisposes the familial patients to cancer
What is Knudson's two hit hypothesis?
That cancer is a multi-hit disease.
In the case of familial retinoblastoma, one hit is hereditary, and one is acquired
What are the mechanisms for loss of heterozygosity (the second hit)?
- Non-disjunction (chromosome loss)
- Nondisjunction and duplication
- Mitotic recombination
- Gene conversion
- Point mutation
- Promoter methylation
What are human tumour supressor genes normally involved in?
Cell cycle and DNA damage control
How was p53 originally identified?
By interactions with viral proteins
Which viral proteins did p53 interact with, leading to its initial discovery?
- Large T antigen of SV40
- E1B of adenovirus
- E6 of papillomavirus
What was p53 first thought to be?
In what % of human cancers is p53 mutated?
What must be true of cancer cells that do not have mutated p53?
p53 must have undergone some form of inactivation
What is Li-Fraumeni syndrome?
A rare, dominant-inherited cancer syndrome where patients have germline mutation in TP53
What kind of protein is p53?
A nuclear phosphoprotein
What is meant by a nuclear phosphoprotein?
Nuclear - found in nucleus
Phosphoprotein - regulated by phosphorylation
What is the function of p53?
It is a transcription factor
In what form does p53 act?
In its tetrameric form
How does p53 act as a transcription factor?
It recognises a 10bp consesus sequence in promoters
Where in the molecule do p53 mutations occur?
They are clustered in exons 5-8
Amino acids 175, 248, and 273 are hotspots
Describe the expression of p53?
It is expressed at very low levels in the absense of damage
What is the half life of p53?
What is the role of p53?
- Main role is to define the cellular response to differnet kinds of damage
- Has many other dunctions, both in response to stress and in normal conditions - some of these functions are antagonistic and simultaneous