Cell and molecular biology of cancer

Question 1

8 hallmarks of cancer

Answer 1

1. Self-sufficiency in growth signals (oncogenes)
2. Insensitivity to anti-growth signals (TSGs)
3. Evasion of apoptosis
4. Replicative immortality
5. Reprogramming of energy metabolism
6. Induce angiogenesis
7. Evasion of immune destruction
8. Tissue invasion and METASTASIS

Question 2

What are the phases of the cell cycle? Give a brief explanation of each phase

Answer 2

1. Mitosis
   - Segregation of chromosomes followed by division to produce 2 daughter cells
2. G1
   - Increase in cell contents (organelles, proteins etc) including replication machinery
3. S
   - Replication of DNA occurs, the chromosomes become two sister chromatids attached at the centromere
4. G2
   - Preparation for division process (more growth)
5. G0
   - Quiescence
   - Cells are not in the cycle, they can return to it and divide if they are able to

Question 3

DNA damage response pathway

Answer 3

When ds or ss breaks are detected, ATM and ATR, respectively, are activated.
ATM and ATR signal downstream to CHK2 and CHK1, respectively, which will induce DNA-damage signal effectors to induce cell cycle arrest, to activate DNA repair machinery or apoptosis.

Question 4

How do oncogenes arise?

Answer 4

1. Abnormal (hyperactive) protein
2. Excessive amounts of normal protein
3. Inappropriate switch on of signalling pathways

Question 5

Which signalling pathways are oncogenes most commonly involved with?

Answer 5

1. Growth factors: PDGF
2. Growth factor receptors: ERBB2
3. G-proteins - RAS
4. Nonreceptor protein kinases - BRAF
5. Transcription factors - MYC
6. Cell cycle and apoptosis regulators - CDK4

Question 6

What are tumour suppressor genes?

Answer 6

Genes whose LOSS or INACTIVATION can trigger the development of cancer

• They normally provide negative control of cell division or apoptosis
• Mutations in TSGs knock out the function
• MUTATION OF BOTH ALLELES is required to promote cancer - one mutant allele can be inherited in rare cases (so only one mutation will lead to tumours)

Question 7

Tumour suppressor genes: Gatekeepers vs caretakers

Answer 7

Gatekeepers: loss directly opens gate to excessive cell proliferation

1. p53: DNA damage checkpoint (induces cell cycle arrest)
2. Rb: controls G1 –> S

Caretakers: maintain genetic stability (DNA repair, chromosome sorting) but are not directly involved in controlling cell proliferation

Question 8

Role of Retinoblastoma

Answer 8

Induces cell cycle arrest by binding to and inactivating TF E2F
- When the cell receives signals to proliferate, G1 CDK2-cyclinA/E complex phosphorylates and inactivates Rb, so E2F can now activate expression of genes involved in cell proliferation

Question 9

Role of P53

Answer 9

• Induces cell cycle arrest in response to DNA damage (activated by ATM)
• Normally, p53 binds MDM2 which causes degradation of p53 via ubiquitination
• ATM phosphorylates p53, so it cannot bind MDM2 and accumulates, it will induce cell cycle arrest and activate DNA repair machinery or induce apoptosis if repair is not possible - it activates transcription of gene PUMA which inhibits an inhibitor of apoptosis Bcl-2, so we get apoptosis of the cell.
• p53 migrates to the nucleus and acts as a TF for p21 which is a CDK inhibitor, it will inhibit the CDK2-cyclin A/E complex so it cannot phosphorylate Rb, and so cell cycle is arrested whilst the DNA is repaired