2) Tumour Suppressors

Question 1

What are the roles of tumour suppressor genes? (3)

Answer 1

Gatekeepers: prevent growth of potential cancer cells
Caretakers: genes that maintain the integrity of the genome, genetic instability if lost
Landscapers: genes that control cellular microenvironment

Question 2

How did Knudson realise the two hit hypothesis?

Answer 2

Investigating retinoblastoma and seeing that familial retinoblastomas appear at a younger age than sporadic (cancer usually takes a long time develop)

Question 3

What are some mechanisms for loss of heterozygosity?

Answer 3

Chromosome loss
Duplication of chromosome 
Mitotic recombination
Gene conversion 
Deletion 
Point mutation

Question 4

What is Li-Fraumeni syndrome?

Answer 4

A rare, dominant-inherited cancer syndrome where patients have germline mutation in TP53 gene

Question 5

What is the function of p53?

Answer 5

Nuclear phosphoprotein that is a transcirption factor in tetrameric form. Recognises sequence on promoters

Question 6

Where do mutations to p53 usually occur?

Answer 6

In exons 5-8, in DNA binding domain

Question 7

How do mutant version of p53 interfere with normal function?

Answer 7

As p53 is a tetramer, at least one mutant subunit renders the p53 functionless

Question 8

When is p53 most active normally?

Answer 8

Responds to cellular damage and stress

Low levels normally

Question 9

How does p53 act as the guardian of the genome?

Answer 9

If the cells has damaged DNA, p53 can cause cell cycle arrest, DNA repair, block angiogenesis and cause apoptosis

Question 10

Describe some post translational modifications to p53 and why they are required:

Answer 10

Attachment of phosphate, acetyl, ubiquityl and methyl groups
Activate molecule and lead to its specific function

Question 11

Explain the p53-mdm2 loop:

Answer 11

p53 induces mdm2 which acts to regulate p53 in a negative feedback loop (prevents function)

Question 12

What are some cellular responses to p53 induction?

Answer 12

Apoptosis, senescene, DNA repair (pro-survival)

Question 13

What is the Warburg effect?

Answer 13

Observation that cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation (can be blocked by p53)

Question 14

Explain p53’s oxidant roles:

Answer 14

Basal levels of p53 are antioxidant, but p53 can use ROS for apoptosis `

Question 15

What is cell senescence?

Answer 15

Permanent cell cycle arrest (cells no longer divide)

Question 16

What are the two pathways to cell senescence?

Answer 16

Replicative senescence

Stress induced premature senescence (SIPS)

Question 17

Why is it advantageous for telomeres to shorten?

Answer 17

Stops old cells, that could be damaged, from dividing

Question 18

What is the problem with many senescent cells?

Answer 18

Accumulation of senescent cells can disrupt tissues, making them less functional. Gives symptoms of ageing

Question 19

What is the function of PTEN?

Answer 19

Dephosphorylates PIP3 to block cell proliferation

Question 20

In what cancers is PTEN often mutated?

Answer 20

Glioblastoma, prostate carcinoma, colon carcinoma, endometrial carcinoma

Question 21

Describe the inheritance pattern of first hit germline mutations:

Answer 21

Autosomal dominant

Question 22

How does PTEN regulate the PI3K pathway?

Answer 22

Converts PIP3 back to PIP2 to prevent cell cycle, protein synthesis and cell growth

Question 23

How do PTEN and p53 collaborate in cells?

Answer 23

p53 + PTEN = apoptosis

p53 - PTEN = senescence