Tumour Suppressor Genes Flashcards
What are tumour suppressor genes?
Alleles which must be inactivated
Both alleles must be mutated, functionally suppressed or lost; TSGs are said to be “recessive” in mechanism to wild-type (inactivation of both alleles)
Critical control and regulatory genes many of which restrain cell proliferation
Transcriptional silencing- methylation/ acetylation
How is Rb (Retinoblastoma Protein) involved in cell cycle control?
controls G1/S restriction checkpoint or R point
When E2F is bound to Rb, no E2F available for transcriptional activation
Phosphorylation of Rb by cyclinD/cdk4,6 complex removes inhibition, E2F activates transcription of itself and cyclinE/cdk2 which further stimulates Rb phosphorylation and more E2F
Why are Rb and E2F so important?
Unphosphorylated Rb sequesters E2F
E2F transcription factors co-ordinately regulate genes that combinatorically promote entry into S phase
Rb/E2F binding on chromatin recruits histone de-acetylases and chromatin remodelling factors to theE2F responsive promoters repressing transcription
Rb phosphorylation releases E2F and initiates E2F dependent transcription
How can the pRb pathway be deregulated?
- mutation or deletion or silencing (by promoter methylation) of p16INK4a
- amplification of Cyclin D1
- mutation/deletion of Rb
What is p53?
Protein, very short half life, very low conc in cells
DNA damage- p53 stabilised and increase conc
Transcription factor, expression of cdk inhibitor P21- inhibits cyclin/cdk complexes
Cell cycle arrest in G1 and G2
Damage severe= pro-apoptotic genes activated (Bax/ Puma), death
Protector against aberrant oncogenes / Guardian of the genome
How does p53 link to cancer?
p53 is mutated in ~ 50% of human cancers
the bioactive form of p53 is a tetramer
if p53 is mutated at one allele then the probability of generating functional tetramers is significantly reduced
a single mutation of p53 therefore results in defects in p53 function and deregulation of pathway
How is p53 regulated?
the INK4a gene encodes 2 potent tumour suppressor genes: p16INK4a and p14ARF
ARF is important in activating p53 in response to abnormal proliferative signals such as inappropriate oncogene activation
ARF protein sequesters mdm2 (the protein that regulates p53 by targeting it for degradation)
p53 is thus upregulated- cell cycle arrest/ apoptosis
What effect does Mutating p53 have?
Makes cell genetically unstable (permits survival and replication of cells that have sustained major DNA damage -double-strand breaks).
“undead” cells are at risk of surviving with: (1) inappropriate recombination events that may activate oncogenes; (2) localised regions of gene amplification, that may promote growth or increase drug resistance
Describe the p53 pathway
Oncogene activation (myc, ras, abl) recognised by ARF, sequesters mdm2, p53 upregulated DNA damage- AT Protein kinase- sequesters mdm2/ activates p53, upregulated Cell cycle arrest (p21)/ apoptosis (Redox gene Bax activated if severe)
How can the Rb and p53 pathways be deregulated?
Rb pathway - Inactivate Rb or p16INK4a - Activate cyclinD or cdk4/6 p53 pathway - Inactivate p53 or ARF - Activate mdm2 Both deregulated= replicative senescence overcome
What are the immortality checkpoints in cancer?
Oncogenic, mutagenic or oxygenic stress- p53 pathway dysfunction- Rb and p53 dysfunction- CRISIS- telomerase upregulated- immortality
