Tumour Suppressors Flashcards
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?
- Gatekeepers
- Caretakers
- Landscapers
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
- Deletion
- 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?
An oncogene
In what % of human cancers is p53 mutated?
50%
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?
20 minutes
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
Do the functions of p53 require the transcription of genes?
Some do (transactivation), some do not
Where do the functions of p53 occur?
Some in the nucleus, some in the cytosol
What kinds of stress does p53 protect against?
- Lack of nucleotides
- UV radiation
- Ionising radiation
- Oncogene signalling
- Hypoxia
- Blockage of transcription
What actions can p53 take to ensure the integrity of the genome?
- Cell cycle arrest
- DNA repair
- Block of angiogensis
- Apoptosis
What can happen to the cell after p53 has induced cell cycle arrest?
- Senescence
- Return to proliferation
What is senescence?
Pernament cell arrest
How is p53 activated?
Post-translational modifications
How is p53 activated?
p53 induces mdm2, which then blocks p53
What are the cellular responses to p53 induction?
- Apoptosis
- Cell cycle arrest, and senescence if prolonged
- DNA repair
- Antiangiogenesis
- Metabolism
- Pro-survival (goes against other functions)
What genes are involved in the p53 apoptotic pathways?
- Bax
- PUMA
- Noxa
- PERP
- Fas
What genes are involved in p53 induced cell cycle arrest and sensecence?
- p21
- GADD45
- Reprimo
How do basal levels of p53 act to aid survival?
They are an anti-oxidant
What is the Warburg effect?
Cancer cells mostly use aerobic glycolysis to obtain energy, instead of oxphos pathway
What kind of energy production do normal cells use?
- Oxidative phosphorylation
- Fatty acid oxidation
What kind of energy production does p53 induce?
- Glycolysis
- Fatty acid oxidation
- Oxidative phosphorylation
What are the types of senescence?
- Replicative senescence
- Stress-induced premature sensecence
What causes replicative senesence?
Short or damaged telomeres
What causes stress-induced premature senescence?
- Oxidative stress
- Activated oncogenes
- Other stresses
What are telomeres?
Repetitive DNA sequences that cap the chromosomes and protects their ends from erosion
What happens to the telomeres with each duplication?
Their ends shorten because duplication is not complete
What effect does telomerase have on telomeres?
They elongate them
What kind of cells possess telomerase?
- Cancer cells
- Stem cells
Draw a diagram illustrating the pathway to senesence
What is the problem with the accumulation of senescent cells?
They disrupt the tissues and so decrease function
What is antagonistic pleiotrophy?
When one gene controls more than one phenotypic trait in an organism (pleitropy), at least one of them is beneficial, and at least one is detrimental to the organisms fitness
What is PTEN?
A tumour suppressor with phosphatase activity
What does PTEN do?
Dephosphorylates PIP3,, and so blocks cell proliferation
What is PIP3?
A signalling molecular of many pro-growth pathways
Where is the PI3K/PTEN pathway commonly inactivated/downregulated?
In many cancers - prostate, lung, brain
What can induce PTEN?
p53
What does p53 and PTEN together lead to?
Apoptosis
What does p53 without PTEN lead to?
Senescence
