Oncogenes

Question 1

TF: oncogenes are recessive

Answer 1

false, they’re dominant. meaning you only need one mutation

Question 2

tumour suppressor genes are divided into two groups, what are these two groups?

Answer 2

recessive- need mutations in both alleles

haploid sufficient- one mutation can cause abnormal growth due to ineffective DNA damage

Question 3

in haploid sufficient genes why is one mutation enough to cause abnormal growth?

Answer 3

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

Question 4

explain the process of retrovirus giving rise to oncoprotein

Answer 4

1. Viron RNA is transcribed into ds DNA in the cell
2. Accidentally transferred truncated DNA provirus is located upstream of the gene
3. A spliced fusion transcript of viral and cellular sequences is packaged into a progeny viron together with a wild-type genome.
4. 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

Question 5

3 mechanisms of proto-oncogene activation?

Answer 5

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

Question 6

philadelphia translocation?

Answer 6

abl C9 becomes joined to bcr C22

Question 7

2 pathways of EGRF

Answer 7

cytoplasmic pathway

nuclear pathway

Question 8

explain the cytoplasmic EGRF pathway?

Answer 8

induces factors which are localised in the cytoplasm which leads to tumorigenesis, proliferation, metastasis, chemoresistance and radio resistance

Question 9

how was the nuclear EGFR pathway be activated

Answer 9

ligand binding

exposure to vitamin D, radiation, heat

Question 10

explain the nuclear EGFR pathway?

Answer 10

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

Question 11

nuclear EGFR interacts with which DNA transcription factors?

Answer 11

E2F1 and STAT3

Question 12

what does interaction of nuclear EGFR and E2F1 and STAT3 induce?

Answer 12

Cyclin D and DNA protein kinase

leads to proliferation and cancer

Question 13

what is c-met

Answer 13

protooncogene producing a transmembrane receptor tyrosine kinase

Question 14

structure of the met receptor?

Answer 14

heterodimer

extracellular alpha subunit with the N-terminal and beta subunit linked by disulphide bonds

Question 15

the beta subunit consists of?

Answer 15

• 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

Question 16

what is the GF needed to bind for c-met signalling?

Answer 16

hepatocyte growth factor

Question 17

what does hepatocyte GF binding to c-met lead to?

Answer 17

c-met homodimerisation and autophosphorylation of intracellular TK’s
phosphorylation leads to recruitment of intracellular signalling molecules

Question 18

met activation induces responses such as RAS, RAF, MEK and eERK/MAPK kinases, what can these all do?

Answer 18

enter the nucleus and module TFs to regulate cell behaviours

Question 19

TF: c-met can cross talk to different membrane proteins? if true give examples and consequence of this

Answer 19

yes
EGFR
plexin B family inter grins
beta catenin 
CD44

consequence: additional signalling response

Question 20

____% of head and neck cancer over express the EGFR

Answer 20

90

Question 21

EGFR over expression has been associated with what?

Answer 21

poorer prognosis and outcomes

Question 22

therapies targeting EGFR? (4)

Answer 22

small molecule TK inhibitors
monoclonal antibodies
PI3K inhibitors
anti-sense gene therapy

Question 23

Gefitinib MOA?

Answer 23

EGFR inhibitor which interrupts signalling through EGFR

Question 24

gefitinib is only effective in which type of cancers?

Answer 24

those which overexpress or have mutated EGFR

Question 25

Trastuzumab MOA?

Answer 25

monoclonal antibody which interfered with HER2 recptor

Question 26

trastuzumab is only effective in which types of cancer?

Answer 26

HER2 over expressing cancers

Question 27

what does the bcr-abl protein do?

Answer 27

TK which is constitutively active.

binds ATP and transfers a phosphate from ATP to tyrosine residues on various substrates

Question 28

effect of bcr-abl on cells?

Answer 28

alteration in adhesion, mitogenic signalling and inhibition of apoptosis

Question 29

how does imatinib work?

Answer 29

TKI block ATP binding to BCR-ABL and inhibits the consequent pathways
reduces excessive myeloid cell proliferation

Question 30

ways to target hepatocyte GF interaction with c-met? (3)

Answer 30

competitive interferences
blocking TK activity of c-met with TKIs
blocking c-met downstream signalling

Question 31

using HGF or c-met specific antibodies does what?

Answer 31

prevents ligand receptor binding resulting in growth inhibition and tumour regression by inhibiting proliferation and enhancing apoptosis

Question 32

using monoclonal ABs allows for what?

Answer 32

exclusive specificity
long half life compared to small molecule KIs
elicit a host immune response against the tumour

Question 33

met monoclonal ABs prevent what? (2)

Answer 33

HGF binding and subsequent c-met phosphorylation

downstream signalling activity

Question 34

how do small molecule kinase inhibitors stir downstream signals?

Answer 34

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