L13 - Tumour Supressor Genes Flashcards
Activation of oncogenes
Leads to proliferation
Inactivation of TSGs
Leads to proliferation
TSGs are involved in cancer when they are
Inactivated or lost
Viral oncogenes have a
Dominant effect
The cancer phenotype is
Recessive
What is the cell fusion technique
Comparison of two alternative alleles and specificed phenotypes when both are forced to co-exist
Dominant allele wins
Growing many nuceli in the same cytoplasm is known as
Heterokaryon
Are hybrid cells able to form tumours
NO
What were the arguments in favour of there being tumour supressor genes
Easier to lose a TSG by mutation than activating an oncogene
SINCE SPECIFIC mutations are required for the gain of funtion
What were the arguements AGAINST the existance of TSGs
2 copies of the TSg must be lost through 2 separate genetic alterations
Complex and thoguh to be improbable to occur in such a short spac of time
What cancer provides genetic eveidence for TSGS
Retinoblastoma
General retinoblastoma
Tumour of the eye
Arrises from photoR precursors
Affects 1:20’000
Diagnosed from birth up to age of 6-8
Two forms of retinoblastom
Sporadic and familial
Sporadic Rb
Develops in children with no family history
Single eye
UNILATERAL
Familial Rb
Children that have a parent who suffered from Rb
Development of multiple foci
BILATERAL RETINOBLASTOMA
Who proposed the two hit hypothesis regarding the formation of retinoblastoma
Knudson
Why is familial both eyes and sporadic a single eye
Familial - higher only need a single event
Sporadic (single eye) - require two random events
Children with WT Rb from both parents require
Two successive alterations in the retinal cell lineage - this is required to inactivate the two functional copies
Children with an Rb mutation inherited from the parents require
A single mutation in the other copy - this is sufficient to be able to drive retinoblastoma
Probability of a single mutagenic event occuring in the first place
10^-6
Probability of 2 successive mutations occuring in the Rb gene
10^-12
How may mitotic recombination be involved with Rb
Chr arm containing the WT allele might be replaced with the one containing the mutant allele
Why is it more likely that mitotic recombination is involved as oposed to mutational inactivation
Occurs at a higher freq (10^-5/4)
What are two ways in which TSGs may function
Direct supression of cell proliferation in resposne to growth-inhibitory and differentiation-idnucing factors
Compoentents of the cellular machinery that inhibits proliferation in response to metabolic imbalance and DNA damage
What were the first two TSGS to be studied
Rb and p53
NF-1 is a
Negative regulator of Ras
Mutations in NF1 can cause
Neurofibromatosis
Neurofibromatosis
Familial cancer
Benign tumour in the PNS
Some progress into neurofibrosarcomas
NF1 encodes a
Ras GAP
What is the action of a Ras GAP
Causes the hydrolysis of GTP terminating signalling
SO when mutated get a consituitvely active rase
What is the result of a mutation in NF1 and the effect on this of the protein produced
Mutations in NF-1 leads to a protein which has a 1000 fold decrease in its ability to stimulate GTP hydrolysis
What percentage of colon cancers are sporadidc
95%
APC
Adenomatous polyposis coli
In the inestinal niche where are stem cells found
Bottom of the crypt
What are the two fates of the stem cell pool
Some remain at the bottom of the crypts to retain the stem cell pool
Most move up as TRANSIT AMPLYIFYING CELLS and are dispatched to the luminal surface of the epithelium
What are some of the defence mechanisms in the I crypt
Even if cells sustain mutations they die within days - this causes no damage to the intestin
Because of the defecne mechanisms what mutation is required to fascilaitate the formation of cancer
Mutations which bock the out migration of cells form the crypt
What is outmigration controlled by
B-catenin which is regulated through Wnt signalling
APC mutations block
The outmigration of cells so they accumulate
APC negatively controls the levels of
cytosolic B catening
Where is APC expressed
Not expressed in the cells at the bottom of the crypt
As cells begin to move upward they express APC
What is the effect of APC not being expressed in the cells of the bottom of the crypt
B catenin is able to accumulate in the nucelus
Molecular consequences of APC inactivation
B catenin is able to accumulate in the cytoplasm and then is able to be translocated to the nucelus
Causes transcription of growth promoting genes including myc
What is VHL
Von Hippen Lindau syndrome
pVHL is important in the modulation of the
Hypoxic resposnse
VHL inactivated in 70% of
sporadic kidney carcinomas
Normoxia is
Normal oxygen tension
Hypoxia is
Subnormal oxygen tension
HIF-1a
Promotes the destruction of the transcription factor HIF-1a
What is the expression of pVHL in tumours
No expression undetectable
Where to mutations occur in the VHL protein
In the amino acid residues in the hydrophobic pocket recogniseing hydroxyproline residues in HIF-1a
The overall consequence of a mutant pVHL at the molecular level is
Conistiuitive activation of HIF-1a TFs
What is the result of conistiuitive activation of HIF-1a TFs
Transcription of growth promoting genes whih stimulate the proliferation of a variety of cell types
