Oncogenes and Tumour Suppressor Genes

Question 1

What are the six hallmarks of cancer?

Answer 1

• Disregard of signals to stop proliferating
• Disregard of signals to differentiate
• Capacity for sustained proliferation
• Evasion of apoptosis
• Ability to invade
• Ability to promote angiogenesis

Question 2

What is gene amplification?

Answer 2

Production of multiple gene copies

Question 3

What are Chimaeric genes?

Answer 3

Genes that are formed by combinations of portions of one or more coding sequence to produce new genes (e.g. the swapping of tips of chromosomes)

Question 4

When can the formation of Chimaeric genes be a problem?

Answer 4

If one of the pieces of translocated DNA is a promoter, it could lead to upregulation of the other gene portion (this occurs in Burkitt’s lymphoma) If the fusion gene codes for an abnormal protein that promotes cancer

Question 5

What is the Philadelphia Chromosome?

Answer 5

Chromosome produced by the translocation of the ABL gene on chromosome 9 to the BCR gene on chromosome 22 The BCR-ABL fusion gene encodes a protein that promotes the development of cancer

Question 6

State some important oncogenes in human cancers.

Answer 6

• SRC – tyrosine kinase
• Myc – transcription factor
• JUN – transcription factor
• Ha-Ras – membrane bound GTPase
• Ki-Ras – membrane bound GTPase

Question 7

What is an example of an inherited cancer?

Answer 7

Retinoblastoma – malignant cancer of the developing retinal cells

Question 8

What mutation causes retinoblastoma?

Answer 8

Due to mutation of the RB1 tumour suppressor gene on chromosome 13q14.

Question 9

State some important tumour suppressor genes in human cancers

Answer 9

P53 – cell cycle regulator BRCA1 – cell cycle regulator PTEN – tyrosine and lipid phosphatase APC – cell signalling

Question 10

In what form is p53 inactive?

Answer 10

When it is bound to MDM2

Question 11

What is p53 important for?

Answer 11

It is important for regulation of p53 target genes: DNA repair growth arrest senescence and important for protein-protein interactions such as apoptosis

Question 12

What is odd about p53 considering it is a tumour suppressor gene?

Answer 12

It acts in a DOMINANT manner –mutation of a single copy is sufficient to achieve dysregulation of activity

Question 13

What deletion causes loss of the APC gene?

Answer 13

5q21

Question 14

What is APC involved in?

Answer 14

Tumour supressor gene involved in: Cell adhesion Cell signalling

Question 15

What is the risk of people with a mutation causing loss of APC developing colon cancer?

Answer 15

90%

Question 16

What is the main role of APC that prevents uncontrolled growth?

Answer 16

APC protein helps control the activity of b-catenin in the WNT signalling pathway and thereby preventing uncontrolled growth.

Question 17

Describe the step-by-step development of colorectal cancer.

Answer 17

1. APC mutations –> hyperproliferative epithelium
2. DNA hypomethylation + K-ras mutation will make the polyps –> adenomas
3. P53 mutation will result in the development of carcinoma

Question 18

What happens in each stage of the cell cycle?

Answer 18

G1:

• Can enter G0 (senescent stage which can enter into G1 when prompted to)
• Growth in mass
• Centrosome duplication

S:

• Chromosome duplication

G2:

• Damage checks

M:

• Mitosis and cytokinesis

Question 19

Where do checks occur in the cell cycle?

Answer 19

G1:

• Restriction point to check for cell size and favourable environmental conditions
• End check for DNA damage

G2:

• Whole phase primarily dedicated to checking for damaged or unduplicated DNA and chromosomes

Question 20

What are the ways an oncogene can be activated?

Answer 20

1. Mutation in the coding sequence e.g. point deletion that generates an abberantly active protein
2. Gene amplification leading to over production of a normal protein
3. Chromosomal translocation leading to chimaeric genes
4. Insertional mutagens e.g. viral infections

Question 21

How can gene amplification occur?

Answer 21

Polymerase encounters an obstruction e.g. a molecule covalently bonded to the DNA then it backs up and repeats the same sequence.

Or insertion of a promoter gene to form and overexpressed chiameric gene

Question 22

How does normal Ras act as a proto-oncogene and how does abberant Ras cause cancer?

Answer 22

Normally:

• Signal received via G protein to initiate cell proliferation
• Adapter protein Grb2 activates Sos
• Sos causes an exchange of GDP for GTP on Ras –> activate Ras
• Ras then activates Raf - the first kinase in the ERK cascade (a cell proliferation pathway)
• Raf-Ras complex activates GAP proteins
• GAP proteins cleave GTP on RAS to GDP
• This deactivates Ras causing Raf to unbind and stop signalling

Mutant Ras:

• Fails to dephosphorylate GTP or Gap cant bind
• Ras remains active.
• Raf remains active
• Constantly signals to proliferate

Question 23

In terms of activation, what is different between most proto-oncogenes and most TSG?

Answer 23

Proto-oncogenes require only 1 of the genes to become abberant for cancer to develop (dominant) TSG require both pairs of the gene to become abberant for cancer (recessive)

Question 24

How is p53 activated?

Answer 24

Many signals for MDM2 to unbind p53:

• Hypoxia
• Oncogene activation
• DNA replicative stress
• Telomere erosion
• Ribonucleotide depltion etc

p53 is released and dimerises to act as a transcriptional factor or to interact with proteins involved in apoptosis