Oncogenes and tumour suppressor genes

Question 1

Oncogenes

Answer 1

Genes which contain alleles that if mutated result in a ‘gain of function’

Act in a dominant function so mutations only need to affect one allele

Normal genes important for growth control that can be activated

Question 2

Proto-oncogenes

Answer 2

Oncogenes which have not been activated

Question 3

Retroviruses contain oncogenes

Answer 3

Due to regular cellular genes being recombined into to the retro viral genome and inappropriately expressed under the powerful viral promoters in long terminal repeats

Question 4

Amplification and truncation - epidermal growth factor EPF-R

Answer 4

Oncogene activation

Can become overactive by the gene being amplified to many 100s of copies in squamous cell carcinomas
OR
If the extracellular domain of the EGF-R is truncated this activates it

Question 5

Point mutation - Ras proto-oncogene

Answer 5

Oncogene activation
When mutated Ras gene becomes constantly activated resulting in uncontrollable proliferation

Mutation occurs in codon 12 -> converts a G base into a T base resulting in a missense mutation as glycine is converted to valine

Question 6

Inappropriate regulation - Burkitts lymphoma

Answer 6

Inappropriate regulation occurs following chromosome translocation

Translocation 8 (where locus for c-myc is) and 14 (where locus for IgG is)

Part of chromosome 14 breaks off and switches with part of chromosome 8 -> resulting in the new chromosome 14 where part of c-myc gene is adjacent to part of IgG gene

Results in loss of normal regulatory sequences of c-myc-> replaced by IgG regulatory sequence

If this occurs in a b-lymphocyte where IgG is highly expressed the result is lymphoma

Question 7

Oncoproteins

Answer 7

Proteins which encode for components of growth signalling pathways

Question 8

erbB - avian erythroblastosis virus

Answer 8

An oncoprotein receptor

An epidermal growth factor

Question 9

Simian sarcoma virus - SIS

Answer 9

Oncoprotein growth factor

A platelet derived growth factor

Question 10

Abelson mouse leukemia virus -abl

Answer 10

Oncoprotein signalling proteins

A tyrosine kinase

Question 11

Rat sarcoma virus -Ras

Answer 11

Oncoprotein - signalling protein

A nucleotide binding molecular switch

Question 12

Myeloctomatosis virus - myc

Answer 12

Oncoprotein transcription factor

Binds DNA stimulates proliferation and regulates apoptosis

Question 13

Tumour suppressor genes

Answer 13

Genes which contain alleles which if mutated results in a loss of function

Both alleles must be mutated - therefore said to be recessive

Critical control and regulatory genes -> many of which restrain cell proliferation/induce DNA repair

Question 14

Rb

Answer 14

Tumour suppressor gene which if both alleles are mutated results in cancer of immature retina cells

Due to the loss of the the wt Rb gene product

Acts as the gatekeeper of the restriction checkpoint (G1)

Phosphorylated by CDK4/Cyclin D

Question 15

Phosphorylated Rb

Answer 15

Inactive so releases E2F

E2F is then free to bind to the RNA and allow transcription of S phase genes

Question 16

E2F

Answer 16

Transcription factor for S phase genes (cyclin E and CDK 2)

Inhibited by unphosphorylated Rb protein binding

Question 17

P16INK4a

Answer 17

CDK inhibitor

Controls cyclin responsible for phosphorylating Rb

Question 18

P53

Answer 18

Protein with very short half life, present in very low concentrations in normal cells

Present as a tetramer - if one of the polypeptides is mutated p53 loses its function

A single mutation of p53 results in defects in p53 function

Question 19

P53 pathway

Answer 19

DNA damage -> [p53] stabilised and increased -> acts as a transcription factor -> induces expression of p21 which inhibits nearly all CDK/cyclin complexes -> leads to cell cycle arrest of both G1 and G2 if damage is reparable -> if damage is severe pro-apoptotic genes are activated and the cell dies

Question 20

Mdm2

Answer 20

Inhibitor of p53

normally leads to rapid degradation of p53 -> maintaining low levels

Question 21

ARF

Answer 21

Can inhibit MDM2

Question 22

AT protein kinase

Answer 22

Phosphorylates mdm2 preventing it from p53

Question 23

Bax

Answer 23

Apoptosis inducting gene

Question 24

Mutating p53 leaves a cell

Answer 24

genetically unstable

Question 25

To overcome replicative senescence

Answer 25

Deregulation of both Rb and p53 is essential