Tumour Supressors Flashcards
What are tumour suppressor genes?
Code for proteins which act to
constrain or suppress cell growth and/or which act to prevent loss of growth control
- Can sense DNA damage and/or inappropriate growth signals
- Act to arrest proliferation and/or induce apoptosis
- Monitor cell cycle checkpoints, Apoptosis, DNA repair, transcription, differentiation, Activation of signalling pathways involved in growth
stimulation - Tumour formation occurs through loss or inactivation by
point mutations, deletions or insertions in these genes
Familial cancer syndromes
Difference between oncogenes and TS
Oncogenes dominant, TS usually recessive. This means both copies
of the TS will need to be inactivated for an effect to be seen
P53
Activated by a range of upstream signals leading to diverse downstream effects
- Displays oncogene like characteristics
- Normal p53 regulates gene expression through binding to its
gene regulatory sites as a tetramer
- P21cip1 is a cell cycle inhibitor protein induced by p53
P53 Pathways
Via growth factors:
- P53 is regulated negatively by MDM2
- When Ras-Myc pathway is over activated, MDM2 inhibitors are produced, therefore no longer able to inhibit P53, allowing it to accumulate
Via DNA damage:
- Highly regulated by PTMs by acetylation and phosphorylation
- When activated by these means, stimulates its target genes leading to cell cycle arrest + apoptosis
P53 Structure
Transactivation Domain - Contains transcription factors
Nuclear localisation signals - Transports it to nucleus
Tetramerisation domain- Forms tetramers
P53 Phenotypes
WT p53 functions as a tetramer to induce gene expression
Mutant p53 leads to the formation of aggregates with loss or gain of function
As WT p53 copies are lost & mutant copies gained, cell susceptibility to cancer increases
What are Micro RNAs?
MiRNA are important in regulating oncogenes and tumour suppressors during development of certain cancers
Retinoblastoma
- Either sporadic or familial
Sporadic = 55-65% of all cases, unilateral
Hereditary childhood cancer:
- bilateral ~75% of cases
- unilateral ~ 25% of cases
Retinoblastoma is inherited as a dominant trait, but is recessive at cellular level.
Those with familial Rb carry 1 mutated gene in all cells, those that get a 2nd hit will develop Rb or other cancers
Children with bilateral (familial) Rb have a high risk of developing non-retinal tumours
Loss of Heterozygosity
pRb Pathway
Central negative regulator of cell cycle
- GF signalling activates CDK46 checkpoint with cyclinD
- Phosphorylates Rb causing release of E2F
- Then activates expression of genes needed for next checkpoint of cell cycle
PTEN
- Negative regulator of PI3Kinase signalling
- Mutated in a lot of cancers
- PTEN loss is not sufficient in for tumour development
PTEN pathway
PTEN works on PIP2 to convert into PIP3, maintains low levels as it is important in cell proliferation
BRCA1/2 Genes
- Function in repair and sensing double strand DNA breaks
- Without these, cells are compromised in their ability for homologous directed repair - information from intact chromosome for a perfect replacement
- Interact with other nuclear proteins
- Non-homologous end joining
BRCA Pathways
APC Pathway
APC is a scaffold protein involved in Wnt signalling. Stops phosphorylation of B-catenin, therefore it can go to nucleus and drive gene expression
In absence of Wnt causes phosphorylation of B-catenin which is then degraded
VHL
In normoxia, HIF1 gets hydroxylated, OH groups recognised by VHL
In hypoxia, HIF1 interacts with HIF1B to form a transcription factor. Drives gene expression of growth factor VEGF which attracts capillaries.
Cancers tend to activate this in kidney through mutations of VHL
