Oncogenes Flashcards
TF: oncogenes are recessive
false, they’re dominant. meaning you only need one mutation
tumour suppressor genes are divided into two groups, what are these two groups?
recessive- need mutations in both alleles
haploid sufficient- one mutation can cause abnormal growth due to ineffective DNA damage
in haploid sufficient genes why is one mutation enough to cause abnormal growth?
the DNA damage repair genes produce proteins that are not at sufficient levels to repair efficiently the extensive DNA damage that usually occurs in cancer cells and this can lead to growth abnormalities
explain the process of retrovirus giving rise to oncoprotein
- Viron RNA is transcribed into ds DNA in the cell
- Accidentally transferred truncated DNA provirus is located upstream of the gene
- A spliced fusion transcript of viral and cellular sequences is packaged into a progeny viron together with a wild-type genome.
- Finally, during next generation reverse transcription recombination between the two genomes generates a DNA provirus composed of the cellular oncogene encoding sequence fused to viral sequences
when activated these oncogenes encode for GF, signalling enzymes or TF;s
3 mechanisms of proto-oncogene activation?
1: mutation or deletion due to carcinogens- altered structured proteins
2: mutations or deletions that occur in the regulatory region of the promoter- increased levels of encoded protein which can lead to cancer
3: errors occurring during division resulting in chromosomal translocation
philadelphia translocation?
abl C9 becomes joined to bcr C22
2 pathways of EGRF
cytoplasmic pathway
nuclear pathway
explain the cytoplasmic EGRF pathway?
induces factors which are localised in the cytoplasm which leads to tumorigenesis, proliferation, metastasis, chemoresistance and radio resistance
how was the nuclear EGFR pathway be activated
ligand binding
exposure to vitamin D, radiation, heat
explain the nuclear EGFR pathway?
Following nuclear translocation, nuclear EGFR interacts with DNA transcription factors E2F1 and STAT3
this induces cyclin D and DNA protein kinase which is involved in DNA repair and radio resistance
nuclear EGFR interacts with which DNA transcription factors?
E2F1 and STAT3
what does interaction of nuclear EGFR and E2F1 and STAT3 induce?
Cyclin D and DNA protein kinase
leads to proliferation and cancer
what is c-met
protooncogene producing a transmembrane receptor tyrosine kinase
structure of the met receptor?
heterodimer
extracellular alpha subunit with the N-terminal and beta subunit linked by disulphide bonds
the beta subunit consists of?
- semaphoring domain
- a plexin- semaphorin intergrin cysteine rich domain
- four immunoglobulins like domains
- transmembrane region
- juxta membrane region
- intracellular tyrosine kinase domain
- C-terminal tail
what is the GF needed to bind for c-met signalling?
hepatocyte growth factor
what does hepatocyte GF binding to c-met lead to?
c-met homodimerisation and autophosphorylation of intracellular TK’s
phosphorylation leads to recruitment of intracellular signalling molecules
met activation induces responses such as RAS, RAF, MEK and eERK/MAPK kinases, what can these all do?
enter the nucleus and module TFs to regulate cell behaviours
TF: c-met can cross talk to different membrane proteins? if true give examples and consequence of this
yes EGFR plexin B family inter grins beta catenin CD44
consequence: additional signalling response
____% of head and neck cancer over express the EGFR
90
EGFR over expression has been associated with what?
poorer prognosis and outcomes
therapies targeting EGFR? (4)
small molecule TK inhibitors
monoclonal antibodies
PI3K inhibitors
anti-sense gene therapy
Gefitinib MOA?
EGFR inhibitor which interrupts signalling through EGFR
gefitinib is only effective in which type of cancers?
those which overexpress or have mutated EGFR
Trastuzumab MOA?
monoclonal antibody which interfered with HER2 recptor
trastuzumab is only effective in which types of cancer?
HER2 over expressing cancers
what does the bcr-abl protein do?
TK which is constitutively active.
binds ATP and transfers a phosphate from ATP to tyrosine residues on various substrates
effect of bcr-abl on cells?
alteration in adhesion, mitogenic signalling and inhibition of apoptosis
how does imatinib work?
TKI block ATP binding to BCR-ABL and inhibits the consequent pathways
reduces excessive myeloid cell proliferation
ways to target hepatocyte GF interaction with c-met? (3)
competitive interferences
blocking TK activity of c-met with TKIs
blocking c-met downstream signalling
using HGF or c-met specific antibodies does what?
prevents ligand receptor binding resulting in growth inhibition and tumour regression by inhibiting proliferation and enhancing apoptosis
using monoclonal ABs allows for what?
exclusive specificity
long half life compared to small molecule KIs
elicit a host immune response against the tumour
met monoclonal ABs prevent what? (2)
HGF binding and subsequent c-met phosphorylation
downstream signalling activity
how do small molecule kinase inhibitors stir downstream signals?
block phosphorylation of the catalytic domain in the receptor by competitive or non-competitive antagonism of the ATP binding site
thereby preventing recruitment of signal transducers and mediators
