Cancer #4 Flashcards
Role of tumour suppressor genes (TSG)
inhibition of cell division via:
~ negative regulation
~ activating cell death
decreases in TSG lead to cancer
Retinoblastoma
most common eye tumour in children ~ routinely checked for - white light shone in eye red = normal white = chance of tumour ~ can be sporadic or hereditary ~ RB tumour suppressor gene affected
Knudson’e two hit mutation hypothesis
retinoblastoma is caused by two mutational events
hereditary = one inherited via germline cells and the 2nd occurs in somatic cells (loss of heterozygosity)
sporadic = both mutations in somatic cells
The cause of loss of heterozygosity is…
homologous recombination in prophase of meiosis I
Role of RB
regulates the passage of cells form G1 to S phase by sequestering E2F
E2F activates genes required for G1/S transition
MUTATED rb/rb cells –> pRB is truncated, unstable so fails to bind to E2F –> cells transition into S phase
p53
transcription factor
a.k.a. guardian of the genome
Li-Fraumeni syndrome
associated with inheritance of a mutated p53 allele
90% risk of developing cancers
p53 functions as a…
tetramer
p53 + no DNA damage
MDM2 ubiquitinates lysine in p53 C-terminal domain = targets it for degradation
~ any remaining p53 is exported from the nucleus
p53 + DNA damage
DNA damage = activates kinases = phosphorylation go MDM2 and p53 (they cannot interact) = p53 tetramerizes and block nuclear export
~ p53 accumulates and interacts with transcription proteins (e.g. p300) –> acetylates histones and p53 = enhanced transcription
~ accumulation of p53 is meant to arrest the cell cycle
Which genes does p53 active the transcription of?
p21 GaDD45 14-3-3sigma Bax APAF1 FAS cell surface death receptors
p21
inhibits cyclin-dependent kinases
arrests cells at G1/S boundary
GaDD45
binds and blocks PCNA
S-phase DNA rep. check point
14-3-3sigma
binds and sequesters CDC25 –> required for activation of cyclinB-cdk1 activation
G2/M boundary
Bax
positive regulator of apoptosis
APAF1
activates camasses = intrinsically apoptosis pathway
FAS cell surface death receptors
extrinsic apoptosis pathway
Loss of wt p53 in tumour cells can lead to…
1) no activation of DNA damage checkpoint
2) no cell cycle arrest
3) apoptosis inhibited
Increased genetic instability leads to…
increased chance of further mutations that may activate oncogenes, or result in loss of tumour suppressor genes
Types of p53 inactivating mutations
1) UV causing C–>T or CC–>TT
2) mutations in DNA bases due to polycyclic hydrocarbons
~ one bad monomer can poison tetramer
~ p53 can also be inactive by its sequestration
Gatekeeper TSGs
directly involved in restraining cell proliferation
e.g. p53, p21, RB and Bax
Caretaker TSGs
maintain the integrity of the genome
e.g. BRCA1, BRCA2
BRCA1 and BRCA2
~ large nuclear proteins
~ promote repair of DNA DSBs by high-fidelity homologous recombination
~ mediated by Rad51
