L13 - Tumour Suppressor Genes Flashcards
(42 cards)
When and how were tumour suppressor genes identified?
1970s-1980s - experimental evidence of a second growth controlling gene - suppress cell proliferation
Tumour suppressor genes involved in cancer when inactivated or lost
Do viral oncogenes have a dominant or recessive effect?
Dominant
Infection of a normal cells results in?
Cell transformation to a cancer cell
Happens despite continued expression of opposite cellular genes that usually mediate normal cell proliferation
Cancerous cell growth - dominant phenotype
Normal cell growth – recessive phenotype
How was it discovered that non-viral oncogenes have a dominant effect?
Cell fusion technique –> comparison of 2 alternative alleles and specified phenotypes when both alleles forced to coexist
- Dominant allele wins
How are two different phenotypes grown together?
Fusing agent is Sendai virus or PEG
The hybrid cell formed is a heterokaryon
What are the two possible outcomes when a cancer cell is fused with a normal cell?
Hybrid cell
Not tumorigenic
- Cancer alleles are recessive - correct pathway
Tumorigenic
- Cancer alleles are dominant
Normal cells carry tumour suppresser genes that constrain their proliferation - inactivated during tumour development
What were the arguments for and against tumour suppressor genes?
For
- Easier to lose a TSG by mutation than activating an oncogene
Against
- 2 copies of TSG must be lost –> 2 genetic alterations complex and unlikely in short period of time
Can’t be addressed with fusion experiment - looked at retinoblastoma
What was looked at to understand the genetic reasons for the recessive phenotype of cancer cells?
Retinoblastoma
Tumour of the retina, arising in photoreceptor precursors
1:20,000 children
Diagnosed from birth up to the age of 6 to 8 years
What are the two forms of retinoblastoma?
Sporadic form
- Children from family with no history of retinoblastoma
- Develop a single tumour in one eye - unilateral
Familial form
- Children with parent who suffered from retinoblastoma
- Develop multiple foci of tumours in both eyes - bilateral
– Elevated susceptibility of developing other tumours
What was Knudson’s 1 hit/2 hits hypothesis used for?
1971 – studied kinetics with which retinal tumours appeared in children affected by retinoblastoma
What were the results of Knudson’s 1 hit/2 hits hypothesis for retinoblastoma?
Rate of appearance of familial tumours - 1 single random event
Rate of appearance of sporadic tumours - 2 random events
Retinoblastoma is caused by a mutation in what gene?
Rb gene
What is needed to cause retinoblastoma in children with wildtype Rb from parents?
2 successive alterations in retinal cell lineage required to inactivate the 2 Rb copies
What is needed to cause retinoblastoma in children with mutant Rb from family?
Mutation of the other copy in enough to drive retinoblastoma
How does sporadic retinoblastoma occur?
Probability of both mutations occurring one after the other is 10-12 per cell generation
More likely to occur due to mitotic recombination
How can mitotic recombination cause retinoblastoma?
Chromosomal arm carrying WT Rb allele replaced with arm carrying mutant allele
Frequency of 10-5 - 10-4 per cell generation - easier than mutational inactivation
Loss of heterozygosity
- Heterozygous phenotype –> homozygous phenotype
What are the two possible ways tumour suppressor genes can stop cancer development?
Direct suppression of cell proliferation in response to growth-inhibitory and differentiation-inducing factors
Components of cellular machinery that inhibit proliferation in response to metabolic imbalance and DNA damage
What are two of the most studied tumour suppressor genes?
Rb and p53
Role in control of the cell cycle disrupted in most human tumours
What are the 3 examples of how tumour suppressor genes function in a diversity of ways?
NF1: negative regulator of Ras signalling
APC: negative regulator of b-catenin signalling
pVHL: negative regulator of HIF-1 transcription factors
What is neurofibromatosis and what is it caused by?
Caused by LOH of NF1
Familial cancer syndrome
Benign tumours in PNS – some progress to malignant neurofibrosarcomas
What is NF1?
Is a Ras GTPase activating protein
What do mutations in NF1 cause?
Create a protein with 1000 fold decrease in GTPase stimulating activity
What happens to NF1 if a cell is stimulated with growth factors?
NF1 degraded - enable Ras signalling to proceed
After 60-90min NF1 levels return to normal - shut down Ras signalling
What happens when NF1 is lost in a cell?
Ras remains activated for longer
Loss of NF1 mimics hyperactivation of Ras observed in presence of mutant ras oncogenes
