Evasion of growth suppressors Flashcards
Tumour supressor genes encode what?
proteins which inhibit cell proliferation
what can happen to TSGs to allow cells to divid uncontrollably
loss
TSGs need to be inactivated where to change the phenotype of the cell?
in both alleles
TF: an individual carrying mutations in tumour suppressor genes in one allele will develop cancer.
false must be in both
functions of TSGs? (3)
inhibit oncogene activation
prevent intracellular signalling
induce expression of genes to slow proliferation or cause cell death
pRb is what? what happens to it in several cancers
tumour suppressor protein
dysfunctional in several cancers
how does pRb prevent excessive cell growth?
prevents cycle progression by binding E2F
What type of phosphorylation do we want on the pRb protein? why?
HYPO- phosphorylated
this is the state it must be in to bind E2F
What happens to pRb (and by what) in cancer development?
phosphorylation by cyclin/ cyclin dependent kinases
results in dissociation of E2F and pRb
enables E2F transcriptional activity
which viruses can inactivate pRb and lead to cancer?
HPV, adenovirus, simian virus
E2F is a family which encodes for what?
family of genes that codifies transcription factors
why is E2F important for DNA synthesis and hence needed for replication?
targets include DHFR enzymes needed for synthesis of purines A and G
E2F induces expression of genes involved in? examples? what does this mean?
apoptosis
caspases 3,7,8
also induces cell death
TF: E2F has only oncogenic characteristics?
false it stimulates DNA synthesis AND cell death
what determines if E2F is going to function as an oncogene or TSG?
microenvironment conditions
what is p53
a TSG
what can happen to the p53 gene to make you PREDISPOSED to cancer?
inherit only one functional copy of the p53 gene from parents
if you inherit only one functional copy of the p53 gene, what do we normally see in early life?
several independent tumours in different tissues
___% of cancer patients have been shown to carry mutations in the p53 TSG.
60
Examples of signals which activate p53? (4)
lack of nucleotides
UV, ionising radiation
hypoxia
transcription blockage
once p53 has been activate what does it act as?
it functions as a TF and binds to DNA to express genes which STOP cell proliferation
example of one of the genes activated p52 acts as a TF towards
p21- a cyclin/ cdk Inhibitor
p21 is a?
cyclin/cdk inhibitor
what happens in mutated p53
can no longer bind to DNA and therefore p21 isn’t produced and there’s no ‘stop’ signals for cell proliferation
uncontrolled cell growth
besides cell cycle arrest, what else is p53 involved in?
DNA damage repair, blocking angiogenesis
stimulation of apoptosis
p53 pathway is _____ in normal cells under normal conditions?
INACTIVE
needs activating by things such as hypoxia, radiation etc
p21 inhibiting cyclin/ cdk maintains ____ being hypo-phosphorylated? meaning?
pRb
the complex between pRb and E2F is maintained
p53 stimulates its own degredation how?
activating MDM2
this activates the proteasome and degraded p53
what do cells expressing high levels of MDM2 have?
low levels of p53 due to it being degraded
how can be target the retinoblastoma tumour suppressor pathway?
inhibiting CDK4 and CDK6
what happens when we inhibit CDK4 and 6 in retinoblastoma?
prevent pRb phosphorylation- maintains the E2F complex
this limits expression of genes required for S phase cell cycle progression
therapeutic strategies at targeting the p53 pathway? (4)
conversion of mutant p52 to form normal properties
prevention of normal p53 interacting with MDM2
gene therapy
exploiting synthetic lethality
