Tumour Supresssor Genes Flashcards
Characteristics of TSG
Protein products of TSG generally function to negatively regulate cell growth and/or cell cycle checkpoints that ensure genomic integrity in response to genotoxic stress
Loss of TSG function means loss of growth suppression and or check point control enhancing proliferative potential
Are TSG dominant or recessive in cancer
Recessive so both alleles must be inactives/removed to stop tumour suppression
This is explained by what hypothesis
Knudson’s two hit hypothesis
Example of retinoblastoma
There is one mutation in the germ line -found in every cell
Only needs 1 random mutation to occur to cause cancer
Tends to cause bilateral retinoblastoma
Early onset of disease
Also increased risk of other cancers such as osteosarcomas
In non hereditary forms - 2 mutation are needed -somatic mutations in a single cell for it to lose its TSG properties and become cancerous
Tends to cause unilateral retinoblastoma
De novo mutations
These can occur in the germ line these lead to familial patterns of inheritance in future generations
What is retinoblastoma
Cancer of the retina
Tumour displaces normal retina
Optic nerve used to metastasise
Symptoms - white light reflection, squint
90% cure rate in developed countries
Bilateral diagnosed early unilateral later diagnosed
Familial inheritance
Large deletions
Single base mutations
Small length mutations
Most mutations are associated with almost complete penetrance
Autosomal dominant
Autosomal dominant at gene level so both alleles need to be inactivated but it is an autodominant disease very likely to get it
Multiple tumors
Somatic mutations
Gene deletions Base substitutions Small length mutations Single tumours, unilateral, later onset Fewer people
How the second mutation occurs
Hypermethylation of the 5’ end affecting RB1
There is inactivation of the promoter that drives expression of Rb
Leads to loss of Rb
Or
Loss of heterozygosity more common
Due to mitotic recombination, mitotic nondysjunction and large deletions
Function of Rb protein in the cell cycle
Rb is important for restriction point control between G1 and S where the cell becomes committed to completing the cell cycle
What drives the cell cycle
Cyclins and CDKs (cyclin dependent kinases)
In the G1 phase CDK4/6 and E-CDK2 are active
pRb is a target for CDK activity
What is pRB function
Transcriptional depressor
What does pRB complex with and what does that do
PRB complexes with E2F family of transcription factors and suppresses their activity
What is HDAC and what does it do?
Histone deacetylases
These down regulate transcription by removing acetyle groups from histones
P300 what is it what does it do
It is an acetylase and oppose the action of HDAC
Add acetyle groups to histones
What happens in early G1 phase
PRB becomes phosphorylated by CDK4/6
This causes dissociation of HDAC
Allow for p300 to act
This then primes the promoter elements for genes that are important in the S phase of the cell cycle
Transcription of these S phase genes are activated
What happens in late G1 phase
CDK2 phosphorylates pRB
This makes pRB move away from E2F
E2F factors drive transcription
What regulates pRb preventing it from allowing the cells cycle move forward into s phase
P16
P16 inhibits CDK 4 dependent phosphorylation of pRb
So pRb remains dephosphorylated and associated with E2F
Inhibiting transcription
Leads to growth and cellular senescence
What is p16ink4a
It is a TSG that can be inactivated in human cancer
If inactivated it cannot inhibit pRb
Leading to its phosphorylation and dissociates from E2F
Activating transcription
Usually happens via a mutation and then epigenetic silencing (both alleles are targeted)
So there is no block to transcription
